Identification of LKB1 mutation as a predictive biomarker for sensitivity to TOR kinase inhibitors

ABSTRACT

Provided herein are methods for treating and/or preventing a cancer or a tumor syndrome in a patient, comprising administering an effective amount of a TOR kinase inhibitor to a patient having cancer or a tumor syndrome, characterized by a LKB1 and/or AMPK gene or protein loss or mutation.

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/301,150, filed Feb. 3, 2010, and claims the benefit of U.S.Provisional Application No. 61/362,982, filed Jul. 9, 2010, the entirecontents of each of which are incorporated herein by reference.

2. FIELD

Provided herein are methods for treating and/or preventing a cancer or atumor syndrome in a patient, comprising administering an effectiveamount of a TOR kinase inhibitor to a patient having cancer or a tumorsyndrome, characterized by a LKB1 and/or AMPK gene or protein loss ormutation.

3. BACKGROUND

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. SeeCohen, Nat. Rev. Drug Disc., 1:309-315 (2002), Grimmiger et al. Nat.Rev. Drug Disc. 9(12):956-970 (2010). Various protein kinase inhibitorshave been used clinically in the treatment of a wide variety ofdiseases, such as cancer and chronic inflammatory diseases, includingdiabetes and stroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001),Protein Kinase Inhibitors for the Treatment of Disease: The Promise andthe Problems, Handbook of Experimental Pharmacology, Springer BerlinHeidelberg, 167 (2005).

The protein kinases belong to a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a critical role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. Malfunctionsof cellular signaling have been associated with many diseases, the mostcharacterized of which include cancer and diabetes. The regulation ofsignal transduction by cytokines and the association of signal moleculeswith protooncogenes and tumor suppressor genes have been welldocumented. Similarly, the connection between diabetes and relatedconditions, and deregulated levels of protein kinases, has beendemonstrated. See e.g., Sridhar et al. Pharm. Res. 17(11):1345-1353(2000). Viral infections and the conditions related thereto have alsobeen associated with the regulation of protein kinases. Park et al. Cell101(7): 777-787 (2000).

Protein kinases can be divided into broad groups based upon the identityof the amino acid(s) that they target (serine/threonine, tyrosine,lysine, and histidine). For example, tyrosine kinases include receptortyrosine kinases (RTKs), such as growth factors and non-receptortyrosine kinases, such as the src kinase family. There are alsodual-specific protein kinases that target both tyrosine andserine/threonine, such as cyclin dependent kinases (CDKs) andmitogen-activated protein kinases (MAPKs).

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as, but notlimited to, cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

Protein kinases have become attractive targets for the treatment ofcancers. Fabbro et al. Pharm. Ther. 93:79-98 (2002). It has beenproposed that the involvement of protein kinases in the development ofhuman malignancies may occur by: (1) genomic rearrangements (e.g.,BCR-ABL in chronic myelogenous leukemia), (2) mutations leading toconstitutively active kinase activity, such as acute myelogenousleukemia and gastrointestinal tumors, (3) deregulation of kinaseactivity by activation of oncogenes or loss of tumor suppressorfunctions, such as in cancers with oncogenic RAS, (4) deregulation ofkinase activity by over-expression, as in the case of EGFR and (5)ectopic expression of growth factors that can contribute to thedevelopment and maintenance of the neoplastic phenotype. Fabbro et al.,Pharm. Ther. 93:79-98 (2002).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways. Accordingly, there remainsa need for new kinase modulators.

The protein named mTOR (mammalian target of rapamycin), also calledFRAP, RAFTI or RAPT1), is a 2549-amino acid Ser/Thr protein kinase, thathas been shown to be one of the most critical proteins in themTOR/PI3K/Akt pathway that regulates cell growth and proliferation.Georgakis and Younes Expert Rev. Anticancer Ther. 6(1):131-140 (2006).mTOR exists within two complexes, mTORC1 and mTORC2. While mTORC1 issensitive to rapamycin analogs (such as temsirolimus or everolimus),mTORC2 is largely rapamycin-insensitive. Notably, rapamycin is not a TORkinase inhibitor. Several mTOR inhibitors have been or are beingevaluated in clinical trials for the treatment of cancer. Temsirolimuswas approved for use in renal cell carcinoma in 2007 and everolimus wasapproved in 2009 for renal cell carcinoma patients that have progressedon vascular endothelial growth factor receptor inhibitors. In addition,sirolimus was approved in 1999 for the prophylaxis of renal transplantrejection. The interesting but limited clinical success of these mTORC1inhibitory compounds demonstrates the usefulness of mTOR inhibitors inthe treatment of cancer and transplant rejection, and the increasedpotential for compounds with both mTORC1 and mTORC2 inhibitory activity.

Somatic mutations affect key pathways in lung cancer. Accordingly,identification of specific mutations associated with lung cancer maylead to improved therapeutic protocols. Recent studies have uncovered alarge number of somatic mutations of the LKB1 gene that are present inlung, cervical, breast, intestinal, testicular, pancreatic and skincancer (Distribution of somatic mutations in STK11, Catalogue of SomaticMutations in Cancer, Wellcome Trust Genome Campus, Hinxton, Cambridge).

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

4. SUMMARY

Provided herein are methods for treating or preventing a cancer, forexample non-small cell lung carcinoma or cervical cancer, or treating atumor syndrome, for example Peutz-Jeghers Syndrome, comprisingadministering an effective amount of a TOR kinase inhibitor to a patienthaving a cancer or a tumor syndrome characterized by a LKB1 gene orprotein loss or mutation, relative to that of a control patient or wildtype.

Further provided herein are methods for treating or preventing a cancer,for example non-small cell lung carcinoma or cervical cancer, comprisingscreening a patient's cancer for the presence of LKB1 gene or proteinloss or mutation relative to that of a control patient or wild type andadministering an effective amount of a TOR kinase inhibitor to thepatient having a cancer characterized by the LKB1 gene or protein lossor mutation.

Further provided herein are methods for detecting LKB1 gene or proteinloss or mutation in a patient's (“test patient”) cancer, for examplenon-small cell lung carcinoma or cervical cancer, comprising: obtaininga biological sample from the test patient's cancer; measuring one ormore of the level of LKB1 mRNA expression, the level of LKB1 proteinexpression, determining the methylation status of the LKB1 gene orotherwise identifying the presence of gene or protein loss or mutation(e.g., by direct cDNA or exon DNA sequencing or SNP analysis or multipleligation probe amplification (MLPA) to identify copy number loss, orimmunohistochemistry (IHC), immunofluorescence (IF) or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient's (“control patient”) cancer which isnot characterized by a LKB1 gene or protein loss or mutation (wildtype); wherein a change in LKB1 mRNA expression, LKB1 proteinexpression, LKB1 mRNA structure, LKB1 gene methylation status and/orLKB1 protein structure in the biological sample from the test patient,relative to that of the control patient or wild-type, indicates thepresence of LKB1 gene or protein loss or mutation in the test patient'scancer.

Further provided herein are methods for predicting the likelihood of apatient having a cancer, for example non-small cell lung carcinoma orcervical cancer, being responsive to TOR kinase inhibitor therapy,comprising screening said patient's cancer for the presence of a LKB1gene or protein loss or mutation relative to that of a control patientor wild type, wherein the presence of LKB1 gene or protein loss ormutation predicts an increased likelihood that TOR kinase inhibitortherapy will treat said cancer.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, with a TOR kinase inhibitor, comprisingscreening said patient's cancer for the presence of LKB1 gene or proteinloss or mutation relative to that of a control patient or wild type,wherein the presence of LKB1 gene or protein loss or mutation in thepatient's cancer is predictive of therapeutic efficacy of treatment witha TOR kinase inhibitor.

Further provided herein are methods for treating a tumor syndrome, forexample Peutz-Jeghers Syndrome, comprising screening the patient for thepresence of a LKB1 gene or protein loss or mutation relative to that ofa control patient or wild type, and administering an effective amount ofa TOR kinase inhibitor to the patient having the LKB1 gene or proteinloss or mutation.

Further provided herein are methods for detecting LKB1 gene or proteinloss or mutation in a patient (“test patient”) having a tumor syndrome,for example, Peutz-Jeghers Syndrome, comprising: obtaining a biologicalsample from the test patient; measuring one or more of the level of LKB1mRNA expression, the level of LKB1 protein expression, determining themethylation status of the LKB1 gene or otherwise identifying thepresence of gene or protein loss or mutation (e.g., by direct cDNA orexon DNA sequencing or SNP analysis or multiple ligation probeamplification (MLPA) to identify copy number loss, orimmunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient (“control patient”) without the LKB1gene or protein loss or mutation (wild type); wherein a change in LKB1mRNA expression, LKB1 protein expression, LKB1 mRNA structure, LKB1 genemethylation status and/or LKB1 protein structure in the biologicalsample from the test patient, relative to that of the control patient orwild-type, indicates the presence of LKB1 gene or protein loss ormutation in the test patient.

Further provided herein are methods for predicting the likelihood of apatient having a tumor syndrome, for example Peutz-Jeghers Syndrome,being responsive to TOR kinase inhibitor therapy, comprising screeningsaid patient for the presence of LKB1 gene or protein loss or mutationrelative to that of a control patient or wild type, wherein the presenceof LKB1 gene or protein loss or mutation predicts an increasedlikelihood that TOR kinase inhibitor therapy will treat said tumorsyndrome.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having a tumor syndrome, for examplePeutz-Jeghers Syndrome, with a TOR kinase inhibitor, comprisingscreening said patient for the presence of LKB1 gene or protein loss ormutation relative to that of a control patient or wild type, wherein thepresence of LKB1 gene or protein loss or mutation in the patient ispredictive of therapeutic efficacy of treatment with a TOR kinaseinhibitor.

Provided herein are methods for treating or preventing a cancer, forexample non-small cell lung carcinoma or cervical cancer, or treating atumor syndrome, for example Peutz-Jeghers Syndrome, comprisingadministering an effective amount of a TOR kinase inhibitor to a patienthaving a cancer or a tumor syndrome characterized by AMPK gene orprotein loss or mutation, relative to that of a control patient or wildtype.

Provided herein are methods for treating or preventing a cancer, forexample non-small cell lung carcinoma or cervical cancer, or treating atumor syndrome, for example Peutz-Jeghers Syndrome, comprisingadministering an effective amount of a TOR kinase inhibitor to a patienthaving a cancer or a tumor syndrome characterized by a reduced level ofphospho-AMPK (pAMPK) protein and/or AMPK activity relative to that of acontrol patient or wild type. In one embodiment, the pAMPK is pAMPKT172.

Further provided herein are methods for treating or preventing a cancer,for example non-small cell lung carcinoma or cervical cancer, comprisingscreening a patient's cancer for the presence of AMPK gene or proteinloss or mutation relative to that of a control patient or wild type, andadministering an effective amount of a TOR kinase inhibitor to thepatient having a cancer characterized by the AMPK gene or protein lossor mutation.

Further provided herein are methods for treating or preventing a cancer,for example non-small cell lung carcinoma or cervical cancer, comprisingscreening a patient's cancer for the presence of a reduced level ofpAMPK protein and/or AMPK activity relative to that of a control patientor wild type, and administering an effective amount of a TOR kinaseinhibitor to the patient having a cancer characterized by a reducedlevel of pAMPK protein and/or AMPK activity. In one embodiment, thepAMPK is pAMPK T172.

Further provided herein are methods for detecting AMPK gene or proteinloss or mutation in a patient's (“test patient”) cancer, for examplenon-small cell lung carcinoma or cervical cancer, comprising: obtaininga biological sample from the test patient's cancer; measuring one ormore of the level of AMPK mRNA expression, the level of AMPK proteinexpression, determining the methylation status of the AMPK gene, orotherwise identifying the presence of gene or protein loss or mutation(e.g., by direct cDNA or exon DNA sequencing or SNP analysis or multipleligation probe amplification (MLPA) to identify copy number loss, orimmunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient's (“control patient”) cancer which isnot characterized by a AMPK gene or protein or mutation (wild type);wherein a change in AMPK mRNA expression, AMPK protein expression, AMPKmRNA structure, AMPK gene methylation, and/or AMPK protein structure inthe biological sample from the test patient, relative to that of acontrol patient or wild type, indicates the presence of AMPK gene orprotein loss or mutation in the test patient's cancer.

Further provided herein are methods for detecting a reduced level ofpAMPK protein and/or AMPK activity in a patient's (“test patient”)cancer, for example non-small cell lung carcinoma or cervical cancer,comprising: obtaining a biological sample from the test patient'scancer; measuring one or more of the level of, pAMPK protein expression,the level of AMPK activity, or otherwise measuring the level of pAMPKprotein (e.g., immunohistochemistry (IHC), immunofluorescence (IF), orWestern Blot to determine the amount of pAMPK protein or the amount ofphosphorylation of AMPK at specific sites, for example at the T172site), and/or the level of AMPK activity (e.g. AMPK kinase assay, seeSanders et al. Biochem. J. 403:139-148 (2007)); and comparing saidmeasurement with a control measurement from a patient's (“controlpatient”) cancer which is not characterized by a reduced level of pAMPKprotein and/or AMPK activity (wild type); wherein a lower level of pAMPKprotein and/or AMPK activity in the biological sample from the testpatient, relative to that of a control patient or wild type, indicatesthe presence of a reduced level of pAMPK protein and/or AMPK activity inthe test patient's cancer.

Further provided herein are methods for predicting the likelihood of apatient having a cancer, for example non-small cell lung carcinoma orcervical cancer, being responsive to TOR kinase inhibitor therapy,comprising screening said patient's cancer for the presence of a AMPKgene or protein loss or mutation, relative to that of a control patientor wild type, wherein the presence of AMPK gene or protein loss ormutation predicts an increased likelihood that TOR kinase inhibitortherapy will treat said cancer.

Further provided herein are methods for predicting the likelihood of apatient having a cancer, for example non-small cell lung carcinoma orcervical cancer, being responsive to TOR kinase inhibitor therapy,comprising screening said patient's cancer for the presence of a reducedlevel of pAMPK protein and/or AMPK activity relative to that of acontrol patient or wild type, wherein the presence of a reduced level ofpAMPK protein and/or AMPK activity predicts an increased likelihood thatTOR kinase inhibitor therapy will treat said cancer.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, with a TOR kinase inhibitor, comprisingscreening said patient's cancer for the presence of AMPK gene or proteinloss or mutation relative to that of a control patient or wild type,wherein the presence of AMPK gene or protein loss in the patient'scancer is predictive of therapeutic efficacy of treatment with a TORkinase inhibitor.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, with a TOR kinase inhibitor, comprisingscreening said patient's cancer for the presence of a reduced level ofpAMPK protein and/or AMPK activity relative to that of a control patientor wild type, wherein the presence a reduced level of pAMPK proteinand/or AMPK activity in the patient's cancer is predictive oftherapeutic efficacy of treatment with a TOR kinase inhibitor.

Further provided herein are methods for treating or preventing cancer,for example non-small cell lung carcinoma or cervical cancer, ortreating a tumor syndrome, for example Peutz-Jeghers Syndrome,comprising administering an effective amount of a TOR kinase inhibitorand an effective amount of one or more agents that modulate AMP levels,glucose uptake, metabolism or a stress response to a patient havingcancer or a tumor syndrome.

Further provided herein are pharmaceutical compositions comprising oneor more TOR kinase inhibitors and one or more agents that modulate AMPlevels, glucose uptake, metabolism or a stress response and apharmaceutically acceptable carrier, excipient or diluent.

Further provided herein are kits comprising one or more containersfilled with a TOR kinase inhibitor or a pharmaceutical compositionthereof, reagents for detecting LKB1 gene or protein loss or mutation,or AMPK gene or protein loss or mutation, or both, in a patient's canceror in a patient having a tumor syndrome and instructions for detectingLKB1 gene or protein loss or mutation, or AMPK gene or protein loss ormutation, or both, in a patient's cancer or in a patient having a tumorsyndrome.

Further provided herein are kits comprising one or more containersfilled with a TOR kinase inhibitor or a pharmaceutical compositionthereof, reagents for detecting a reduced level of pAMPK protein and/orAMPK activity in a patient's cancer or in a patient having a tumorsyndrome, and instructions for detecting a reduced level of pAMPKprotein and/or AMPK activity in a patient's cancer or in a patienthaving a tumor syndrome.

In some embodiments, the TOR kinase inhibitor is a compound as describedherein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A. FIG. 1 lists the LKB1 mutation status of non small cell lungcancer (NSCLC) cell lines, based on reported DNA sequences, the reportedmutation, the presence (positive) or absence (negative) of intact LKB1protein (as determined by Western immunoblotting as shown in FIG. 1B)and mean IC₅₀ values (μM) for growth inhibition by Compound 1 (n isnumber of replicate IC₅₀ determinations).

FIG. 1B. FIG. 1B illustrates a LI-COR Western blot showing LKB1 proteinlevels across the panel of NSCLC cell lines from FIG. 1A. The experimentconfirms lack of LKB1 protein for lines reported as LKB1 gene mutants.

FIG. 2A. FIG. 2A illustrates the correlation of sensitivity to TORkinase inhibitor Compound 1 treatment (IC₅₀) with reported LKB1 genemutation status, as determined by Kruskal test (p=0.0296).

FIG. 2B. FIG. 2B illustrates the correlation of sensitivity to TORkinase inhibitor Compound 1 treatment (IC₅₀) with the presence(positive) or absence (negative) of LKB1 protein as assessed by LI-CORWestern immunoblotting, as determined by the Wilcoxon test (p=0.0128).

FIG. 2C. FIG. 2C illustrates the application of the Fisher test andWilcoxon test to analyze the correlation between Compound 1 sensitivity(defined as IC₅₀<5 μM) and the presence or absence of intact LKB1protein (as determined by Western immunoblotting). The resultingp-values indicate that cell lines without intact LKB1 protein are moresensitive to Compound 1.

FIG. 3A. FIG. 3A illustrates a LI-COR Western blot showing phospho-AMPKT172, AMPK, LKB1, and actin levels from selected NSCLC cell lines. TheLKB1 protein levels are correlated to pAMPK T172 levels except forH1437.

FIG. 3B. FIG. 3B illustrates the result of the application of theWilcoxon test to analyze the correlation between LKB1 status andpAMPK/actin ratio in forty-two NSCLC cell lines. LKB1 status was definedas either negative or positive based on Western immunoblotting. They-axis is Log₁₀ of pAMPK/actin ratio. The correlation between LKB1protein status and pAMPK/actin ratio was assessed using Wilcoxon test(p=0.000278), wherein a p value <0.05 is considered as significantcorrelation.

6. DETAILED DESCRIPTION 6.1 Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃)and —CH₂C≡C(CH₇CH₃), among others. An alkyl group can be substituted orunsubstituted. Unless otherwise indicated, when the alkyl groupsdescribed herein are said to be “substituted,” they may be substitutedwith any substituent or substituents as those found in the exemplarycompounds and embodiments disclosed herein, as well as halogen (chloro,iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino;alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide;amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonato;phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone;aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine;aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide;isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2,or O(alkyl)aminocarbonyl.

An “alkenyl” group is a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms, typically from 2 to 8carbon atoms, and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₈)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl and the like. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. An alkenylgroup can be unsubstituted or substituted.

A “cycloalkyl” group is a saturated, partially saturated, or unsaturatedcyclic alkyl group of from 3 to 10 carbon atoms having a single cyclicring or multiple condensed or bridged rings which can be optionallysubstituted with from 1 to 3 alkyl groups. In some embodiments, thecycloalkyl group has 3 to 8 ring members, whereas in other embodimentsthe number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as adamantyl and the like. Examples of unsaturated cycloalkylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanone and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl (for example,isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl(for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example,azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocyclylalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase heterocyclyl includes fused ringspecies, including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. Representative examples of aheterocyclyl group include, but are not limited to, aziridinyl,azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl;for example, 1H-imidazo[4,5-b]pyridyl, or1H-imidazo[4,5-b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed below.

An “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tocyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and cyclohexylpropyl. Representative substituted cycloalkylalkyl groupsmay be mono-substituted or substituted more than once.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

A “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyrdine-3-yl methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl,tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl.

A “halogen” is fluorine, chlorine, bromine or iodine.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amino” group is a radical of the formula: —NH₂.

An “alkylamino” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

A “carboxy” group is a radical of the formula: —C(O)OH.

An “aminocarbonyl” group is a radical of the formula: —C(O)N(R^(#))₂,—C(O)NH(R^(#)) or —C(O)NH₂, wherein each R^(#) is independently asubstituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl,heterocyclyl or heterocyclyl group as defined herein.

An “acylamino” group is a radical of the formula: —NHC(O)(R^(#)) or—N(alkyl)C(O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

An “alkylsulfonylamino” group is a radical of the formula: —NHSO₂(R^(#))or —N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(O)N(R^(#))₂,—N(alkyl)C(O)NH(R^(#)), —N(alkyl)C(O)NH₂, —NHC(O)N(R^(#))₂,—NHC(O)NH(R^(#)), or —NH(CO)NHR^(#), wherein each alkyl and R^(#) areindependently as defined above.

When the groups described herein, with the exception of alkyl group, aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonato; phosphine; thiocarbonyl; sulfonyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide;hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate;oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl,piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fusedor non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl,pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl,quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of the TORkinase inhibitors include, but are not limited to metallic salts madefrom aluminum, calcium, lithium, magnesium, potassium, sodium and zincor organic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,phosphoric, sulfuric, and methanesulfonic acids. Examples of specificsalts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “clathrate”means a TOR kinase inhibitor, or a salt thereof, in the form of acrystal lattice that contains spaces (e.g., channels) that have a guestmolecule (e.g., a solvent or water) trapped within or a crystal latticewherein a TOR kinase inhibitor is a guest molecule.

As used herein and unless otherwise indicated, the term “solvate” meansa TOR kinase inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. In one embodiment, the solvate is ahydrate.

As used herein and unless otherwise indicated, the term “hydrate” meansa TOR kinase inhibitor, or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “prodrug” meansa TOR kinase inhibitor derivative that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a TOR kinase inhibitor.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a TOR kinase inhibitor that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6^(th) ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a TOR kinaseinhibitor that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The TOR kinaseinhibitors can have chiral centers and can occur as racemates,individual enantiomers or diastereomers, and mixtures thereof. All suchisomeric forms are included within the embodiments disclosed herein,including mixtures thereof. The use of stereomerically pure forms ofsuch TOR kinase inhibitors, as well as the use of mixtures of thoseforms are encompassed by the embodiments disclosed herein. For example,mixtures comprising equal or unequal amountsv of the enantiomers of aparticular TOR kinase inhibitor may be used in methods and compositionsdisclosed herein. These isomers may be asymmetrically synthesized orresolved using standard techniques such as chiral columns or chiralresolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racematesand Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., etal., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind., 1972).

It should also be noted the TOR kinase inhibitors can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the TOR kinase inhibitors are isolatedas either the cis or trans isomer. In other embodiments, the TOR kinaseinhibitors are a mixture of the cis and trans isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of the TOR kinase inhibitors are within the scope of thepresent invention.

It should also be noted the TOR kinase inhibitors can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with deuterium (²H),carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein, an “isotopologue”is an isotopically enriched compound. The term “isotopically enriched”refers to an atom having an isotopic composition other than the naturalisotopic composition of that atom. “Isotopically enriched” may alsorefer to a compound containing at least one atom having an isotopiccomposition other than the natural isotopic composition of that atom.The term “isotopic composition” refers to the amount of each isotopepresent for a given atom. Radiolabeled and isotopically encrichedcompounds are useful as therapeutic agents, e.g., cancer andinflammation therapeutic agents, research reagents, e.g., binding assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the TOR kinase inhibitors as described herein,whether radioactive or not, are intended to be encompassed within thescope of the embodiments provided herein. In some embodiments, there areprovided isotopologues of the TOR kinase inhibitors, for example, theisotopologues are deuterium, carbon-13, or nitrogen-15 enriched TORkinase inhibitors.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease (e.g., cancer or a tumorsyndrome), or slowing, or halting of further progression or worsening ofthose symptoms.

“Preventing” as used herein, means the prevention of the onset,recurrence or spread, in whole or in part, of the disease or disorder(e.g., cancer), or a symptom thereof.

The term “effective amount” in connection with an TOR kinase inhibitormeans an amount capable of alleviating, in whole or in part, symptomsassociated with cancer, for example non-small cell lung carcinoma orcervical cancer, or a tumor syndrome, for example Peutz-JeghersSyndrome, or slowing or halting further progression or worsening ofthose symptoms, or preventing or providing prophylaxis for cancer, forexample non-small cell lung carcinoma or cervical cancer, or a tumorsyndrome, for example Peutz-Jeghers Syndrome in a subject at risk forcancer, for example non-small cell lung carcinoma or cervical cancer, ora tumor syndrome, for example Peutz-Jeghers Syndrome. The effectiveamount of the TOR kinase inhibitor, for example in a pharmaceuticalcomposition, may be at a level that will exercise the desired effect;for example, about 0.005 mg/kg of a subject's body weight to about 100mg/kg of a patient's body weight in unit dosage for both oral andparenteral administration. As will be apparent to those skilled in theart, it is to be expected that the effective amount of a TOR kinaseinhibitor disclosed herein may vary depending on the severity of theindication being treated.

The terms “patient” and “subject” as used herein include an animal,including, but not limited to, an animal such as a cow, monkey, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig, in one embodiment a mammal, in another embodiment a human.

As used herein “wild type” refers to the typical or most common form ofa characteristic (for example, gene sequence or presence, or proteinsequence, presence, level or activity), as it occurs in nature, and thereference against which all others are compared. As will be understoodby one skilled in the art, when used herein, wild type refers to thetypical sequence of LKB1 gene or protein or AMPK gene or protein, or thetypical level of LKB1 gene or protein, AMPK gene or protein, pAMPKprotein, or AMPK activity, as it most commonly occurs in nature.Similarly, a “control patient”, as used herein, is a patient whopossesses the wild type characteristics (presence, sequence, level,activity) for LKB1 and/or AMPK. For example, as used herein “LKB1 geneor protein mutation” refers to, for example, a LKB1 gene mutationresulting in a decrease in LKB1 mRNA expression, a decrease in LKB1protein production or a non-functional LKB1 protein, as compared to wildtype. As used herein “LKB1 gene or protein loss” refers to a reducedlevel of LKB1 protein or the absence of LKB1 protein, as compared towild type levels.

As used herein, “AMPK activity” refers to the activity of AMP-activatedprotein kinase. As understood by one skilled in the art, AMPK requiresactivation by phosphorylation to exert its kinase activity. In thecontext of AMPK activity, it is understood that AMPK activity and pAMPKactivity can be used interchangeably.

As used herein “reduced level” or “loss” means a reduction in levelrelative to levels observed in wild type. In one embodiment thereduction is 10%-50% or 50%-100%. In some embodiments, the reduction is20%, 30%, 40%, 50%, 60%, 70%, 80%. 90% or 100% (complete loss) relativeto wild type.

In one embodiment, a “patient” or “subject” is a human whose cancer DNAcomprises a LKB1 and/or an AMPK gene mutation, relative to that of acontrol patient or wild type. In another embodiment, a “patient” or“subject” is a human whose cancer DNA contains a LKB1 and/or an AMPKgene mutation, relative to that of a control patient or wild type. Inanother embodiment, a “patient” or “subject” is a human whose cancer DNAcomprises a LKB1 and/or an AMPK gene mutation and a KRAS gene mutation,relative to that of a control patient or wild type. In anotherembodiment, a “patient” or “subject” is a human having a cancer, forexample non-small cell lung carcinoma or cervical cancer, characterizedby LKB1 and/or AMPK gene or protein loss or mutation, relative to thatof a control patient or wild type. In another embodiment, a “patient” or“subject” is a human having a cancer, for example non-small cell lungcarcinoma or cervical cancer, characterized by LKB1 and/or AMPK gene orprotein loss or mutation and a KRAS gene mutation, relative to that of acontrol patient or wild type.

In another embodiment, a “patient” or “subject” is a human whose DNAcomprises a LKB1 and/or an AMPK gene mutation, relative to that of acontrol patient or wild type. In another embodiment, a “patient” or“subject” is a human whose DNA contains a LKB1 and/or an AMPK genemutation, relative to that of a control patient or wild type. In anotherembodiment, a “patient” or “subject” is a human whose DNA comprises aLKB1 and/or an AMPK gene mutation and a KRAS gene mutation, relative tothat of a control patient or wild type. In another embodiment, a“patient” or “subject” is a human having LKB1 and/or AMPK gene orprotein loss or mutation, relative to that of a control patient or wildtype. In another embodiment, a “patient” or “subject” is a human havingLKB1 and/or AMPK gene or protein loss or mutation, relative to that of acontrol patient or wild type, and also having a tumor syndrome, forexample Peutz-Jeghers Syndrome. In another embodiment, a “patient” or“subject” is a human having LKB1 and/or AMPK gene or protein loss ormutation and a KRAS gene mutation, relative to that of a control patientor wild type, wherein said human also has a tumor syndrome, for examplePeutz-Jeghers Syndrome.

In another embodiment, a “patient” or “subject” is a human having acancer, for example non-small cell lung carcinoma or cervical cancer,characterized by a reduced level of pAMPK protein and/or AMPK activity,relative to that of a control patient or wild type. In anotherembodiment, a “patient” or “subject” is a human having a cancer, forexample non-small cell lung carcinoma or cervical cancer, characterizedby a reduced level of pAMPK protein and/or AMPK activity and a KRAS genemutation, relative to that of a control patient or wild type. In someembodiments, the pAMPK is pAMPK T172.

In another embodiment, a “patient” or “subject” is a human having areduced level of pAMPK protein and/or AMPK activity, relative to that ofa control patient or wild type, and also having a tumor syndrome, forexample Peutz-Jeghers Syndrome. In another embodiment, a “patient” or“subject” is a reduced level of pAMPK protein and/or AMPK activity and aKRAS gene mutation, relative to that of a control patient or wild type,wherein said human also has a tumor syndrome, for example Peutz-JeghersSyndrome. In some embodiments, the pAMPK is pAMPK T172.

In the context of cancer, for example non-small cell lung carcinoma orcervical cancer, or a tumor syndrome, for example Peutz-JeghersSyndrome, inhibition may be assessed by delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, among others. In the extreme, complete inhibition,is referred to herein as prevention or chemoprevention. In this context,the term “prevention” includes either preventing the onset of clinicallyevident cancer, carcinoma or tumor altogether or preventing the onset ofa preclinically evident stage of cancer, carcinoma or tumor inindividuals at risk. Also intended to be encompassed by this definitionis the prevention of transformation into malignant cells or to arrest orreverse the progression of premalignant cells to malignant cells. Thisincludes prophylactic treatment of those at risk of developing thecancer, carcinoma or tumor.

6.2 TOR Kinase Inhibitors

The compounds provided herein are generally referred to as TOR kinaseinhibitors or “TORKi.” In a specific embodiment, the TORKi do notinclude rapamycin or rapamycin analogs (rapalogs). In certainembodiments, compounds provided herein are also DNA-PK inhibitors or“DNA-PKi.”

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (I):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

X, Y and Z are at each occurrence independently N or CR³, wherein atleast one of X, Y and Z is N and at least one of X, Y and Z is CR³;

-A-B-Q- taken together form —CHR⁴C(O)NH—, —C(O)CHR⁴NH—, —C(O)NH—,—CH₂C(O)O—, —C(O)CH₂O—, —C(O)O— or C(O)NR³;

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R³ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclylalkyl, —NHR⁴ or —N(R⁴)₂; and

R⁴ is at each occurrence independently substituted or unsubstitutedC₁₋₈alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (I) are thosewherein -A-B-Q- taken together form —CH₂C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)CH₂NH—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —CH₂C(O)O—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)CH₂O—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)O—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NR³—.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein Y is CR³.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Z are N and Y is CR³.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Z are N and Y is CH.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Z are CH and Y is N.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein Y and Z are CH and X is N.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein X and Y are CH and Z is N.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is C₁₋₄alkyl substituted with substituted orunsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl, L is a direct bond, and R² is substituted orunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl, L is a direct bond, andR² is substituted or unsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl, and R² is C₁₋₈alkylsubstituted with one or more substituents selected from alkoxy, amino,hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted or unsubstituted aryl, and R² is substituted orunsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) arethose wherein -A-B-Q- taken together form —C(O)NH—, X and Z are N and Yis CH, R¹ is substituted phenyl, L is a direct bond, and R² issubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, and R² is C₁₋₈alkyl substitutedwith substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is phenyl, naphthyl, indanyl orbiphenyl, each of which may be optionally substituted with one or moresubstituents independently selected from the group consistingsubstituted or unsubstituted C₁₋₈alkyl, substituted or unsubstitutedC₂₋₈alkenyl, substituted or unsubstituted aryl, substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is phenyl, naphthyl or biphenyl, eachof which may be optionally substituted with one or more substituentseach independently selected from the group consisting of C₁₋₄alkyl,amino, aminoC₁₋₁₂alkyl, halogen, hydroxy, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, —CF₃, C₁₋₁₂alkoxy, aryloxy, arylC₁₋₁₂alkoxy, —CN,—OCF₃, —COR_(g), —COOR_(g), —CONR_(g)R_(h), —NR_(g)COR_(h), —SO₂R_(g),—SO₃R_(g) or —SO₂NR_(g)R_(h), wherein each R_(g) and R_(h) areindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₃₋₆cycloalkyl, aryl, arylC₁₋₆alkyl, heteroaryl or heteroarylC₁₋₆alkyl;or A is a 5- to 6-membered monocyclic heteroaromatic ring having fromone, two, three or four heteroatoms independently selected from thegroup consisting of N, O and S, that monocyclic heteroaromatic ring maybe optionally substituted with one or more substituents eachindependently selected from the group consisting of C₁₋₆alkyl, amino,aminoC₁₋₁₂alkyl, halogen, hydroxy, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₁₂alkoxy, aryloxy, aryl C₁₋₁₂alkoxy, —CN,—CF₃, —OCF₃, —COR_(i), —COOR_(i), —CONR_(i)R_(j), —NR_(i)COR_(j),—NR_(i)SO₂R_(j), —SO₂R_(i), —SO₃R₁, or —SO₂NR_(i)R_(j), wherein eachR_(i) and R_(j) are independently selected from the group consisting ofhydrogen, C₁₋₄ alkyl, C₃₋₆cycloalkyl, aryl, arylC₁₋₆alkyl, heteroaryl orheteroarylC₁₋₆alkyl; or A is a 8- to 10 membered bicyclic heteroaromaticring from one, two, three or four heteroatoms selected from the groupconsisting of N, O and S, and may be optionally substituted with one,two or three substituents each independently selected from the groupconsisting of C₁₋₆alkyl, amino, aminoC₁₋₁₂alkyl, halogen, hydroxy,hydroxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₁₂alkoxy, aryloxy, arylC₁₋₁₂alkoxy, —CN, —CF₃, —OCF₃, —COR_(k), —COOR_(k), —CONR_(k)R₁,—NR_(k)COR₁, —NR_(k)SO₂R₁, —SO₂R_(k), —SO₃R_(k) or —SO₂NR_(k)R₁, whereineach R_(k) and R₁ are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl, arylC₁₋₆alkyl,heteroaryl or heteroarylC₁₋₆alkyl, and R² is C₁₋₈alkyl substituted withsubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Y are both N and Z is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is substituted or unsubstituted phenylor substituted or unsubstituted heteroaryl, and R² is substituted orunsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or anacetamide.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Y are both N and Z is CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is substituted or unsubstituted phenylor substituted or unsubstituted heteroaryl, and R² is an acetamide.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X is N and Y and Z are both CH, -A-B-Q- is—C(O)NH—, L is a direct bond, R¹ is a(2,5′-Bi-1H-benzimidazole)-5-carboxamide, and R² is H.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein one of X and Z is CH and the other is N, Y isCH, -A-B-Q- is —C(O)NH—, L is a direct bond, R¹ is unsubstitutedpyridine, and R² is H, methyl or substituted ethyl.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NH—, R¹ is H, C₁₋₈alkyl, C₂₋₈alkenyl, aryl or cycloalkyl, and L isNH.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein X and Z are both N and Y is CH, -A-B-Q- is—C(O)NR³—, R² is H, substituted or unsubstituted C₁₋₈alkyl, substitutedor unsubstituted phenyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclylalkyl, and L is NH.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude compounds wherein R¹ is a substituted or unsubstitutedoxazolidinone.

In another embodiment, the TOR kinase inhibitors of formula (I) do notinclude one or more of the following compounds:1,7-dihydro-2-phenyl-8H-Purin-8-one,1,2-dihydro-3-phenyl-6H-Imidazo[4,5-e]-1,2,4-triazin-6-one,1,3-dihydro-6-(4-pyridinyl)-2H-Imidazo[4,5-1)]pyridin-2-one,6-(1,3-benzodioxol-5-yl)-1,3-dihydro-1-[(1S)-1-phenylethyl]-2H-Imidazo[4,5-b]pyrazin-2-one,3-[2,3-dihydro-2-oxo-3-(4-pyridinylmethyl)-1H-imidazo[4,5-b]pyrazin-5-yl]-Benzamide,1-[2-(dimethylamino)ethyl]-1,3-dihydro-6-(3,4,5-trimethoxyphenyl)-2H-Imidazo[4,5-b]pyrazin-2-one,N-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-N′-[4-(1,2,3,4-tetrahydro-2-oxopyrido[2,3-b]pyrazin-7-yl)-1-naphthalenyl]-Urea,N-[4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-6-yl)-1-naphthalenyl]-N′-[5-(1,1-dimethylethyl)-2-methoxyphenyl]-Urea,1,3-dihydro-5-phenyl-2H-Imidazo[4,5-b]pyrazin-2-one,1,3-dihydro-5-phenoxy-2H-Imidazo[4,5-b]pyridin-2-one,1,3-dihydro-1-methyl-6-phenyl-2H-Imidazo[4,5-b]pyridin-2-one,1,3-dihydro-5-(1H-imidazol-1-yl) 2H-Imidazo[4,5-b]pyridin-2-one,6-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-6-yl)-8-methyl-2(1H)-Quinolinoneand 7,8-dihydro-8-oxo-2-phenyl-9H-purine-9-acetic acid.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ia):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

Y is N or CR³;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R³ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclylalkyl, —NHR⁴ or —N(R⁴)₂; and

R⁴ is at each occurrence independently substituted or unsubstitutedC₁₋₈alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ia) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein Y is CH.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ia) do notinclude compounds wherein Y is CH, L is a direct bond, R¹ is substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl, and R²is C₁₋₈alkyl substituted with substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ib):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ib) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ib) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ic):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ic) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ic) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Id):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Id) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the Heteroaryl Compounds of formula (Id) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Id) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ie):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ie) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ie) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (If):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (If) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (If) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (Ig):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

L is a direct bond, NH or O;

R¹ is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted C₂₋₈alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocyclylalkyl; and

R² is H, substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In one embodiment, the TOR kinase inhibitors of formula (Ig) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl or substituted or unsubstitutednaphthyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted quinoline, substituted or unsubstitutedpyridine, substituted or unsubstituted pyrimidine, substituted orunsubstituted indole, or substituted or unsubstituted thiophene.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is H.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is substituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is methyl or ethyl substituted with substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R² is H.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl and R² isunsubstituted C₁₋₈alkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl and R² isC₁₋₈alkyl substituted with one or more substituents selected fromalkoxy, amino, hydroxy, cycloalkyl, or heterocyclylalkyl.

In another embodiment, the TOR kinase inhibitors of formula (Ig) arethose wherein R¹ is substituted or unsubstituted aryl and R² issubstituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl.

Representative TOR kinase inhibitors of formula (I) include:

-   (S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((tetrahydro-2H-pyran-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-6-(naphthalen-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(3-methoxybenzyl)-6-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-hydroxyphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-6-(naphthalen-1-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-hydroxy-3-methylbutan-2-yl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-hydroxy-3-methylbutan-2-yl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-benzyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(4-methoxybenzyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-isopropyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-cyclohexyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-isobutyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(2-hydroxyethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one;-   (S)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one;-   3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   (R)-3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   (R)-6-(5-isopropyl-2-methoxyphenyl)-1-(3-methylbutan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-6-(5-isopropyl-2-methoxyphenyl)-1-(3-methylbutan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-cyclopentyl-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydrofuran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(cyclopropylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(cyclopentylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(cyclohexylmethyl)-6-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(5-isopropyl-2-methoxyphenyl)-1-neopentyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-isopropyl-6-(3-isopropylphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-isopropyl-6-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-3-(1-hydroxy-3-methylbutan-2-yl)-5-(5-isopropyl-2-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   (R)-1-(2-hydroxy-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-(2-hydroxy-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-benzhydryl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-(1-phenylpropyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-phenylpropyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(5-isopropyl-2-methoxyphenyl)-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(3-methoxybenzyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-methyl-3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-1-methyl-3-(1-phenylethyl)-5-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(cyclopentylmethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(2-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(4-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-cyclopentyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(3-fluorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(3-methoxyphenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(4-methoxyphenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(quinolin-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(quinolin-5-yl)-1-(tetrahydro-2H-pyran-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((1s,4s)-4-hydroxycyclohexyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((1r,4r)-4-hydroxycyclohexyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(isoquinolin-5-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-(1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   1-isopropyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(4-chlorophenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(4-(methylsulfonyl)phenyl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(pyridin-4-yl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   5-methyl-1-((S)-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   5-methyl-1-((R)-1-phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-phenylethyl)-6-(quinolin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-fluorophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(2-fluorophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-phenylethyl)-6-(quinolin-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(piperidin-4-ylmethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(pyridin-2-yl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-(pyridin-3-yl)ethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((1s,4s)-4-(hydroxymethyl)cyclohexyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   N-(4-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide;-   6-(3-(methylsulfonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-aminophenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-(dimethylamino)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-phenyl-6-(quinolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(1-phenylethyl)-6-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   N-(3-(2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)methanesulfonamide;-   6-(4-(methylsulfonyl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   3-(1-phenylethyl)-5-(quinolin-5-yl)oxazolo[5,4-b]pyrazin-2(3H)-one;-   1-(cyclopentylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one-   6-(4-hydroxyphenyl)-1-isopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-hydroxyphenyl)-1-isobutyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-hydroxyphenyl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(cyclohexylmethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   5-(3-Hydroxyphenyl)-3-(2-methoxyphenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   4-(3-(3-Methoxybenzyl)-2-oxo-2,3-dihydrooxazolo[5,4-b]pyrazin-5-yl)-N-methyl    benzamide;-   1-Cyclopentyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-Cyclohexyl-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;-   Methyl    4-(3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoate;-   1-(Cyclohexylmethyl)-6-(pyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-methylbenzamide;-   1-(Cyclohexylmethyl)-6-(4-(hydroxymethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile;-   1-(Cyclohexylmethyl)-6-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-isopropylbenz    amide;-   1-(2-Hydroxyethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(1H-indol-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   3-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;-   6-(4-(Aminomethyl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile;-   1-((1s,4s)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(pyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-N-ethylbenzamide;-   1-(Cyclohexylmethyl)-6-(4-(2-hydroxypropan-2-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(4-hydroxy-2-methylphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzoic    acid;-   6-(4-Hydroxyphenyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(3-methoxypropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-Hydroxyphenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-phenethyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((1r,4r)-4-Hydroxycyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-phenyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(1-oxoisoindolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-(1H-Tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(2-oxoindolin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(1H-indazol-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(6-methoxypyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(((1r,4r)-4-Aminocyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(6-hydroxypyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(2-methoxypyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-((1r,4r)-4-Hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;-   2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetic    acid;-   2-(4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)phenyl)acetamide;-   1-(Cyclohexylmethyl)-6-(2-oxoindolin-6-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(3-(Cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-3-methyl    benzoic acid;-   N-Methyl-4-(2-oxo-3-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;-   4-(2-oxo-3-((Tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;-   7-(4-Hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-Hydroxypropan-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-Indol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-Benzo[d]imidazol-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(2-oxo-3-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzamide;-   6-(3-(2H-1,2,3-Triazol-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Imidazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(2H-tetrazol-5-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(2-hydroxypyridin-4-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Imidazol-2-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(2-Hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(4-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Pyrazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Pyrazol-4-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-(Aminomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   1-(Cyclohexylmethyl)-6-(4-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((1r,4r)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((1r,4r)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((1s,4s)-4-methoxycyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((1r,4r)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1-Methyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(((1r,4r)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(((1s,4s)-4-Hydroxycyclohexyl)methyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-Benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   6-(4-(5-(Morpholinomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(3-(2-oxopyrrolidin-1-yl)propyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   1-(Cyclohexylmethyl)-6-(4-(oxazol-5-yl)phenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(2-Methyl-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   6-(4-(5-(Methoxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-((1s,4s)-4-(Hydroxymethyl)cyclohexyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-Methyl-1H-pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-Pyrazol-4-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(2-Amino-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    di hydrochloride;-   6-(4-(5-(2-Hydroxypropan-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-Isopropyl-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   4-(2-Methoxy-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide    hydrochloride;-   4-(1-((1s,4s)-4-Hydroxycyclohexyl)-2-methoxy-1H-imidazo[4,5-b]pyrazin-6-yl)benzamide;-   6-(4-Hydroxyphenyl)-1-((1s,4s)-4-(methoxymethyl)cyclohexyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3H-imidazo[4,5-b]pyridin-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(2-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)ethyl)-6-(4-hydroxyphenyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Pyrazol-1-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Benzo[d]imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-Imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,    5-1)]pyrazin-2(3H)-one;-   6-(4-(1H-Imidazol-5-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   6-(4-Hydroxyphenyl)-1-((5-oxopyrrolidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4,5-Dimethyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,4-Triazol-5-yl)phenyl)-1-(((1s,4s)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,4-Triazol-5-yl)phenyl)-1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-(1H-1,2,4-Triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-((dimethylamino)methyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   6-(2-Aminobenzimidazol-5-yl)-1-(cyclohexylmethyl)-4-imidazolino[4,5-b]pyrazin-2-one    di hydrochloride;-   6-(2-(Dimethylamino)-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-(piperidin-3-ylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   1-(Cyclohexylmethyl)-6-(2-(methylamino)pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(2-(2-methoxyethylamino)pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-((methylamino)methyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-Oxopyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methyl-2-morpholinopropyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(1-morpholinopropan-2-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(Pyrrolidin-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-(aminomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(5-(Hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (1r,4r)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclo-hexanecarboxamide;-   (1s,4s)-4-(6-(4-Hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide;-   6-(4-(5-methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-Oxopyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(Pyrrolidin-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-benzo[d]imidazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(3-(Hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(5-(2-Hydroxyethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(pyrimidin-5-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-Fluoropyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-Aminopyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-methyl-1H-imidazol-2-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-Methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-(Methylamino)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(2-aminopyrimidin-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-hydroxyphenyl)-1-((1-methylpiperidin-3-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   1-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(hydroxymethyl)thiophen-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-benzo[d]imidazol-6-yl)-1-(((1r,4r)-4-methoxycyclohexyl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4,5-dimethyl-1H-imidazol-2-yl)phenyl)-1-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;-   (R)-6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (S)-6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (1r,4r)-4-(6-(4-(2-hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide;-   6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one;-   6-(4-(1H-imidazol-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(5-(Aminomethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(1H-benzo[d]imidazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(2-Aminopyrimidin-5-yl)-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-Hydroxyphenyl)-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one    hydrochloride;-   6-(3-Methyl-4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one;-   1-(Cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(6-(2-Hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(2-morpholino-2-oxoethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (R)-6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-B]pyrazin-2(3H)-one;-   (S)-6-(4-(4H-1,2,4-Triazol-3-yl)phenyl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one;-   (1r,4r)-4-(6-(4-(2-Hydroxypropan-2-yl)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclohexanecarboxamide;    and-   6-(4-(5-Methyl-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one,    and pharmaceutically acceptable salts, clathrates, solvates,    stereoisomers, tautomers, and prodrugs thereof.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (II):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

—X-A-B—Y— taken together form —N(R²)CH₂C(O)NH—, —N(R²)C(O)CH₂NH—,—N(R²)C(O)NH—, —N(R²)C═N—, or —C(R²)═CHNH—;

L is a direct bond, NH or O;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (II) are thosewherein —X-A-B—Y— taken together form —N(R²)CH₂C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)CH₂NH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C═N—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —C(R²)═CHNH—.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein L is a direct bond.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R¹ issubstituted aryl, such as phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R¹ issubstituted or unsubstituted heteroaryl, such as substituted orunsubstituted pyridine, substituted or unsubstituted indole orsubstituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R¹ issubstituted or unsubstituted cycloalkyl, such as substituted orunsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH— and R² isunsubstituted aryl, such as unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted heteroaryl, such as substituted orunsubstituted pyridine, and R² is substituted or unsubstituted aryl,such as substituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted heteroaryl, such as substituted orunsubstituted pyridine, R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, L is a directbond, R¹ is substituted or unsubstituted heteroaryl, such as substitutedor unsubstituted pyridine, R² is substituted or unsubstituted aryl, suchas substituted or unsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted aryl, such as substituted or unsubstitutedphenyl, and R² is substituted or unsubstituted aryl, such as substitutedor unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted aryl, such as substituted or unsubstitutedphenyl, R² is substituted or unsubstituted aryl, such as substituted orunsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, L is a directbond, R¹ is substituted or unsubstituted aryl, such as substituted orunsubstituted phenyl, R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl, and R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted heteroaryl, L is a direct bond and R² issubstituted or unsubstituted C₁₋₈alkyl or substituted or unsubstitutedcycloalkyl.

In another embodiment, the TOR kinase inhibitors of formula (II) arethose wherein —X-A-B—Y— taken together form —N(R²)C(O)NH—, R¹ issubstituted or unsubstituted aryl, L is a direct bond and R² issubstituted or unsubstituted C₁₋₈alkyl or substituted or unsubstitutedcycloalkyl.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-purine-6-carboxamide,2-(4-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,2-(4-nitrophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,9-benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide,2-methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,9-benzyl-9H-purine-2,6-dicarboxamide,9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2-methyl-9H-Purine-6-carboxamide,9-benzyl-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-methyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,2-methyl-9-phenylmethyl-9H-purine-6-carboxamide or2-methyl-9-β-D-ribofuranosyl-9H-purine-6-carboxamide.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude compounds wherein R² is a substituted furanoside.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude compounds wherein R² is a substituted or unsubstitutedfuranoside.

In another embodiment, the TOR kinase inhibitors of formula (II) do notinclude (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IIa):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IIa) are thosewherein R¹ is substituted aryl, substituted or unsubstituted heteroaryl,such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IIa) arethose wherein R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide,8,9-dihydro-8-oxo-9-phenyl-2-(3-pyridinyl)-7H-Purine-6-carboxamide,2-(4-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,2-(4-nitrophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide,9-benzyl-2-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide,9-phenylmethyl-9H-purine-2,6-dicarboxamide, or2-methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude compounds wherein R² is a substituted furanoside.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude compounds wherein R² is a substituted or unsubstitutedfuranoside.

In another embodiment, the TOR kinase inhibitors of formula (IIa) do notinclude (2′R)-2′-deoxy-2′-fluoro-2′-C-methyl nucleosides.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IIb):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

is —C(R²)═CH—NH— or —N(R²)—CH═N—;

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IIb) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R³ and R⁴ are H.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein

is —C(R²)═CH—NH— and R² is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein

is —N(R²)—CH═N— and R² is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) arethose wherein R¹ is substituted aryl, such as phenyl, and R² issubstituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude 9-benzyl-9H-purine-2,6-dicarboxamide,9-[2,3-bis[(benzoyloxy)methyl]cyclobutyl]-2-methyl-9H-Purine-6-carboxamide,9-benzyl-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-methyl-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-(prop-1-enyl)-9H-purine-6-carboxamide,9-(2-hydroxyethyl)-2-phenyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-methyl-9H-purine-6-carboxamide,9-(3-hydroxypropyl)-2-(trifluoromethyl)-9H-purine-6-carboxamide,9-phenylmethyl-9H-purine-2,6-dicarboxamide,2-methyl-9-phenylmethyl-9H-purine-6-carboxamide or2-methyl-9-β-D-ribofuranosyl-9H-purine-6-carboxamide.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted cyclobutyl when

is —N(R²)—CH═N—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is a substituted furanoside when

is —N(R²)—CH═N—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted pyrimidine when

is —C(R²)═CH—NH—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted oxetane when

is —N(R²)—CH═N—.

In another embodiment, the TOR kinase inhibitors of formula (IIb) do notinclude compounds wherein R² is substituted cyclopentyl or aheterocyclopentyl when

is —N(R²)—CH═N—.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IIc):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IIc) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IIc) arethose wherein R³ and R⁴ are H.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IId):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is substituted or unsubstituted C₁₋₈alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocyclylalkyl; and

R³ and R⁴ are independently H or C₁₋₈alkyl.

In one embodiment, the TOR kinase inhibitors of formula (IId) are thosewherein R¹ is substituted aryl, such as substituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R¹ is substituted or unsubstituted heteroaryl, such assubstituted or unsubstituted pyridine, substituted or unsubstitutedindole or substituted or unsubstituted quinoline.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R¹ is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclopentyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted C₁₋₈alkyl, such as —CH₂C₆H₅.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is unsubstituted C₁₋₈alkyl, such as unsubstitutedmethyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted or unsubstituted aryl, such assubstituted or unsubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted aryl, such as halo, haloalkyl or alkoxysubstituted phenyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted or unsubstituted cycloalkyl, such assubstituted or unsubstituted cyclohexyl or substituted or unsubstitutedcycloheptyl.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R² is substituted heterocyclylalkyl, such as substitutedpiperidine.

In another embodiment, the TOR kinase inhibitors of formula (IId) arethose wherein R³ and R⁴ are H.

Representative TOR kinase inhibitors of formula (II) include:

-   9-benzyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   N-methyl-8-oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   8-oxo-9-phenyl-2-(pyridin-2-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(2-chloropyridin-3-yl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide;-   2-(2-methoxypyridin-3-yl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide;-   N,N-dimethyl-8-oxo-9-phenyl-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-methyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-hydroxyphenyl)-8-oxo-9-o-tolyl-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-indol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-indol-6-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-hydroxyphenyl)-9-(4-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(2-hydroxypyridin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-chlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2,6-difluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-cycloheptyl-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-methoxyphenyl)-8-oxo-2-(quinolin-5-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-cyclopentyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-methoxyphenyl)-8-oxo-2-(3-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-methoxyphenyl)-2-(6-methoxypyridin-3-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-hydroxyphenyl)-8-oxo-9-(4-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-benzyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-hydroxyphenyl)-8-oxo-9-(2-(trifluoromethoxy)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2,4-dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-methoxyphenyl)-2-(3-nitrophenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-cyanophenyl)-8-oxo-9-phenyl-8,9-dihydro-7H-purine-6-carboxamide;-   9-(3-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-methoxyphenyl)-8-oxo-2-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(5-fluoropyridin-3-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1-benzylpiperidin-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;    benzyl    4-(6-carbamoyl-8-oxo-2-(pyridin-3-yl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate;-   9-cyclohexyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-methoxyphenyl)-8-oxo-2-(3-(trifluoromethoxy)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-phenyl-2-(pyridin-3-yl)-9H-purine-6-carboxamide;-   6-oxo-8-phenyl-2-(pyridin-3-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;-   6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxamide;-   2-(3-aminophenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-hydroxyphenyl)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide;-   9-Cyclopentyl-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-tert-Butyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   [2-(3-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo(7-hydropurin-6-yl)]-N-methylcarbox-amide;-   2-phenyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide;-   [2-(3-Hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo(7-hydropurin-6-yl)]-N,N-dimethyl    carboxamide;-   2-(3-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(trans-4-Hydroxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(trans-4-Hydroxycyclohexyl)-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(trans-4-Hydroxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(trans-4-Hydroxycyclohexyl)-8-oxo-2-(pyridin-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenylamino)-9-(2-methoxyphenyl)-9H-purine-6-carboxamide;-   9-Isopropyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   Methyl    4-(6-carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate;-   2-(2-Chloro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(3-Cyanophenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(2-Hydroxyphenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-9-(4-methoxy-2-methylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-Cyano-phenyl)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   4-[6-Carbamoyl-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl]-benzoic    acid;-   Methyl    3-(6-carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoate;-   3-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)benzoic    acid;-   2-(3-Hydroxyphenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Indazol-6-yl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(4-Carbamoylphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Ethylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2,5-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(3-Carbamoylphenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2,6-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(2-Hydroxyphenyl)-9-(2-methoxyphenyl)purine-6-carboxamide;-   2-(1H-Indazol-5-yl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2,3-Dichlorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-[4-(Hydroxymethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;-   2-[3-(Hydroxymethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;-   9-(2-Methoxyphenyl)-8-oxo-2-(pyridin-4-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-Fluoro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;-   2-(2-Fluoro-3-hydroxyphenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;-   2-[4-(1-Hydroxy-isopropyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-[3-(1-Hydroxy-isopropyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2-Methoxyphenyl)-2-(2-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2-Methoxyphenyl)-2-(4-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2-Methoxyphenyl)-2-(2-nitrophenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2,4-Difluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2-Methoxyphenyl)-2-{3-[(methylsulfonyl)amino]phenyl}-8-oxo-7-hydropurine-6-carboxamide;-   9-(4-Chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2-Chlorophenyl)-8-oxo-2-(3-pyridyl)-7-hydropurine-6-carboxamide;-   8-Oxo-2-(3-pyridyl)-9-[2-(trifluoromethyl)phenyl]-7-hydropurine-6-carboxamide;-   9-(3-Chloro-2-fluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2-Fluoro-3-trifluoromethylphenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(2,3,4-Trifluorophenyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(1H-Benzo[d]imidazol-6-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-[3-(Acetylamino)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(3-hydroxyphenyl)-8-(2-methoxyphenyl)-6-oxo-5,6,7,8-tetrahydropteridine-4-carbox-amide;-   9-(2-Methoxyphenyl)-8-oxo-2-pyrazol-4-yl-7-hydropurine-6-carboxamide;-   9-(2-Methoxyphenyl)-8-oxo-2-pyrazol-3-yl-7-hydropurine-6-carboxamide;-   9-(4-Aminocyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-[3-(Difluoromethyl)phenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carbox-amide;-   2-[5-(Difluoromethyl)-2-fluorophenyl]-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(1H-benzo[d]imidazol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(6-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-benzo[d]imidazol-6-yl)-9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-Benzimidazol-6-yl-8-oxo-9-[2-(trifluoromethyl)phenyl]-7-hydropurine-6-carboxamide;-   2-(5-Chloropyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   trans-4-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)    cyclohexyl carbamate;-   (R)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxamide;-   (S)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxamide;-   (cis)-4-(6-Carbamoyl-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)    cyclohexyl carbamate;-   2-(trans-4-Hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-Chloropyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(cis-4-Hydroxycyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-((1H-Imidazol-1-yl)methyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   (R)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxamide;-   (S)-9-(2-Methoxyphenyl)-8-oxo-2-(pyrrolidin-2-ylmethylamino)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(2-Hydroxyethylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Methoxyphenyl)-8-oxo-2-(2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-methoxyphenyl)-8-oxo-7-hydropurine-6-carboxamide;-   9-(Biphenyl-2-yl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-fluorophenyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Methoxyphenyl)-2-(2-methyl-1H-benzo[d]imidazol-6-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-(Hydroxymethyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(2-(Hydroxymethyl)phenylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-tert-Butylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-8-oxo-9-(2-phenoxyphenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Benzo[d]imidazol-6-yl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Indazol-4-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(2-Hydroxypyridin-3-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-Imidazol-1-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Cyclohexylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-Imidazol-2-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Benzo[d]imidazol-1-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Isopropylphenyl)-8-oxo-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Imidazo[4,5-b]pyridin-6-yl)-8-oxo-9-(2-(trifluoromethyl)phenyl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Methoxyphenyl)-2-(2-(methylthio)-1H-benzo[d]imidazol-5-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Indol-5-yl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(Cyclohexylmethyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2,3-Dihydro-1H-inden-1-yl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-9-isobutyl-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(trans-4-Methoxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(cis-4-Methoxycyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-8-oxo-9-(5,6,7,8-tetrahydronaphthalen-1-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-cyclohexyl-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-9-(1H-indol-4-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Fluoro-3-methoxyphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Fluoro-5-methoxyphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-Cyclohexyl-2-(1H-imidazo[4,5-b]pyridin-6-yl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Cyclopentylphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-8-oxo-9-(piperidin-4-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   9-(2-Fluoro-4-methoxyphenyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-benzo[d]imidazol-6-yl)-9-cyclohexyl-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-Benzimidazol-6-yl-9-(trans-4-methoxycyclohexyl)-8-oxo-7-hydropurine-6-carboxamide;-   2-(4-(Aminomethyl)phenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-9-(cis-4-(methoxymethyl)cyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   9-(trans-4-Aminocyclohexyl)-2-(3-hydroxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-9-(2-isobutylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   (R)-2-(3-Hydroxyphenyl)-8-oxo-9-(tetrahydrofuran-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   (S)-2-(3-Hydroxyphenyl)-8-oxo-9-(tetrahydrofuran-3-yl)-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-(Aminomethyl)phenyl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-1,2,3-Triazol-5-yl)phenyl)-9-(2-isopropylphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(4-(1H-1,2,4-Triazol-3-yl)phenyl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Benzo[d]imidazol-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;-   2-(3-Hydroxyphenyl)-9-((1r,4r)-4-(methoxymethyl)cyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide;    and-   9-(2-Isopropylphenyl)-2-(4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide,    and pharmaceutically acceptable salts, clathrates, solvates,    stereoisomers, tautomers, and prodrugs thereof.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (III):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ and R⁴ are each independently H, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aralkyl,substituted or unsubstituted cycloalkylalkyl, or R³ and R⁴, togetherwith the atoms to which they are attached, form a substituted orunsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;

or R² and one of R³ and R⁴, together with the atoms to which they areattached, form a substituted or unsubstituted heterocyclyl,

wherein in certain embodiments, the TOR kinase inhibitors do not includethe compounds depicted below, namely:

-   6-(4-hydroxyphenyl)-4-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;

-   6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    or,

-   (R)-6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3-(cyclohexylmethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one

In some embodiments of compounds of formula (III), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. In oneembodiment, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl,indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, substituted or unsubstituted triazolyl or pyrazolyl), halogen(for example, fluorine), aminocarbonyl, cyano, hydroxyalkyl (forexample, hydroxypropyl), and hydroxy. In other embodiments, R¹ ispyridyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl (for example, substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl,—OR, and —NR₂, wherein each R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl. In yet other embodiments, R¹ is1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, each optionally substitutedwith one or more substituents independently selected from the groupconsisting of substituted or unsubstituted C₁₋₈ alkyl, and —NR₂, whereineach R is independently H, or a substituted or unsubstituted C₁₋₄ alkyl.

In some embodiments of compounds of formula (III), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl, halogen (forexample, fluorine), cyano, —OR, or —NR₂; m is 0-3; and n is 0-3. It willbe understood by those skilled in the art that any of the substituentsR′ may be attached to any suitable atom of any of the rings in the fusedring systems. It will also be understood by those skilled in the artthat the connecting bond of R¹ (designated by the bisecting wavy line)may be attached to any of the atoms in any of the rings in the fusedring systems.

In some embodiments of compounds of formula (III), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR, or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (III), R² is H, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In some such embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In some other embodiments of compounds of formula (III), R² and one ofR³ and R⁴ together with the atoms to which they are attached form asubstituted or unsubstituted heterocyclyl. For example, in someembodiments, the compound of formula (III) is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R″ is H, OR, or a substituted or unsubstitutedC₁₋₄ alkyl; and R¹ is as defined herein.

In some embodiments of compounds of formula (III), R³ and R⁴ are both H.In others, one of R³ and R⁴ is H and the other is other than H. In stillothers, one of R³ and R⁴ is C₁₋₄ alkyl (for example, methyl) and theother is H. In still others, both of R³ and R⁴ are C₁₋₄ alkyl (forexample, methyl).

In some such embodiments described above, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl, indolyl,indazolyl, 1H-pyrrolo[2,3-b]pyridyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, halogen, aminocarbonyl,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of cyano, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, hydroxyalkyl, halogen,aminocarbonyl, —OR, and —NR₂, wherein each R is independently H, or asubstituted or unsubstituted C₁₋₄ alkyl. In others, R¹ is1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl, optionally substituted withone or more substituents independently selected from the groupconsisting of substituted or unsubstituted C₁₋₈ alkyl, and —NR₂, whereinR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (III) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (III), the compound at aconcentration of 10 μM inhibits mTOR, DNA-PK, or PI3K or a combinationthereof, by at least about 50%. Compounds of formula (III) may be shownto be inhibitors of the kinases above in any suitable assay system.

Representative TOR kinase inhibitors of formula (III) include:

-   6-(1H-pyrrolo[2,3-b]pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-ethyl-6-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(2-methoxyethyl)-6-(4-methyl-6(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-(2-methoxyethyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   3-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzonitrile;-   5-(8-(trans-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   6-(1H-imidazo[4,5-b]pyridin-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1R,3S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1S,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1R,3R)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-((1S,3S)-3-methoxycyclopentyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-ethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(((1R,3S)-3-methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(((1S,3R)-3-methoxycyclopentyl)methyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(4-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3S)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3R)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1R,3S)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(((1S,3R)-3-methoxycyclopentyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)-1′H-spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′-((tetrahydro-2H-pyran-4-yl)methyl)-1′H-spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   4-(cyclopropylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopentane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclobutane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   7′-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1′H-spiro[cyclopropane-1,2′-pyrazino[2,3-b]pyrazin]-3′(4′H)-one;-   (R)-6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(1H-indazol-5-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(6-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   4-(2-methoxyethyl)-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-ethyl-3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)-2-methylpyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(1-hydroxyethyl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3,3-dimethyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cis-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(trans-4-methoxycyclohexyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(2-methoxyethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(6-(4H-1,2,4-triazol-3-yl)-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-(cis-4-methoxycyclohexyl)-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-6-methylpicolinonitrile;-   6-(6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyacetyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-(2-methoxyethyl)-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   4-(cyclopentylmethyl)-6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(6-(4H-1,2,4-triazol-3-yl)-2-methyl-3-pyridyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   4-(trans-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cis-4-hydroxycyclohexyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cyclopentylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-neopentyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-isobutyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-methyl-6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(piperidin-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-3-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(3aS,2R)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2R,3aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3    aR)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)(2S,3aS)-2-methoxy-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydrofuran-2-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-3-methyl-6,11,4a-trihydropiperazino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)phenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydropiperidino[1,2-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(cyclohexylmethyl)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(tetrahydrofuran-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-phenyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-[6-(1-hydroxy-isopropyl)-3-pyridyl]-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-amino-7-methyl-1H-benzo[d]imidazol-5-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   9-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-6,11,4a-trihydromorpholino[4,3-e]pyrazino[2,3-b]pyrazin-5-one;-   6-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   8-(4-(4H-1,2,4-triazol-3-yl)-2-methylphenyl)-5,10,3a-trihydropyrazino[2,3-b]pyrrolidino[1,2-e]pyrazin-4-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-methyl-1H-benzo[d]imidazol-6-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   6-(4-(2-hydroxypropan-2-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    and-   6-(4-(1H-1,2,4-triazol-5-yl)phenyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,    and pharmaceutically acceptable salts, clathrates, solvates,    stereoisomers, tautomers, and prodrugs thereof.

In one embodiment, the TOR kinase inhibitors include compounds havingthe following formula (IV):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, and prodrugs thereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl,

wherein in certain embodiments, the TOR kinase inhibitors do not include7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,depicted below:

In some embodiments of compounds of formula (IV), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, a substituted or unsubstituted triazolyl or pyrazolyl),aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl andhydroxy. In other embodiments, R¹ is pyridyl substituted with one ormore substituents independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl (for example, methyl),substituted or unsubstituted heterocyclyl (for example, a substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl(for example, hydroxypropyl), —OR, and —NR₂, wherein each R isindependently H, or a substituted or unsubstituted C₁₋₄ alkyl. In someembodiments, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In some embodiments, R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl (for example,methyl), halogen (for example, fluoro), cyano, —OR, or —NR₂; m is 0-3;and n is 0-3. It will be understood by those skilled in the art that anyof the substituents R′ may be attached to any suitable atom of any ofthe rings in the fused ring systems.

In some embodiments of compounds of formula (IV), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (IV), R² is H, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In other embodiments of compounds of formula (IV), R² is H, C₁₋₄ alkyl,(C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In other embodiments of compounds of formula (IV), R³ is H.

In some such embodiments described herein, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine,pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl,or pyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₈ alkyl, substituted or unsubstituted heterocyclyl,halogen, aminocarbonyl, cyano, hydroxyalkyl, —OR, and —NR₂, wherein eachR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl. Instill others, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (IV) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (IV), the compound at aconcentration of 10 μM inhibits mTOR, DNA-PK, PI3K, or a combinationthereof by at least about 50%. Compounds of formula (IV) may be shown tobe inhibitors of the kinases above in any suitable assay system.

Representative TOR kinase inhibitors of formula (IV) include:

-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(methylamino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxycyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine    1-oxide;-   4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;-   5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;-   1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    and-   1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,    and pharmaceutically acceptable salts, clathrates, solvates,    stereoisomers, tautomers, and prodrugs thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound having thefollowing formula:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer,tautomer, or prodrug thereof.

In one embodiment, the TOR kinase inhibitor is a compound disclosed inWO 2008/023161 (see, e.g., page 5, line 5 to page 11, line 15), WO2009/007751 (see, e.g., page 9, line 8 to page 26, line 8), WO2009/007749 (see, e.g., page 9, line 21 to page 29, line 23), WO2009/007750 (see, e.g., page 9, line 21 to page 32, line 22), WO2009/007748 (see, e.g., page 9, line 6 to page 42, line 28), WO2008/032028 (see, e.g., page 11, line 13 to page 21, line 13), WO2008/032086 (see, e.g., page 10 line 21 to page 15, line 22), WO2008/032072 (see, e.g., page 11, line 11 to page 16, line 13), WO2008/032033 (see, e.g., page 11, line 3 to page 16, line 5), WO2008/032089 (see, e.g., page 11, line 11 to page 16, line 13), WO2008/032060 (see, e.g., page 11, line 3 to page 16, line 6), WO2008/032091 (see, e.g., page 11, line 11 to page 16, line 13), WO2008/032036 (see, e.g., page 11, line 13 to page 21, line 13), WO2008/032077 (see, e.g., page 10, line 21 to page 15, line 22), WO2008/032064 (see, e.g., page 11, line 3 to page 16, line 5), WO2008/032027 (see, e.g., page 10, line 21 to page 15, line 22), WO2007/135398 (see, e.g., page 11, line 28 to page 16, line 6), WO2007/129052 (see, e.g., page 10, line 8 to page 13, line 5), WO2007/129044 (see, e.g., page 10, line 22 to page 13, line 20), WO2007/080382 (see, e.g., page 9, line 20 to page 32, line 32), WO2007/066102 (see, e.g., page 9, line 22 to page 14, line 17), WO2007/066099 (see, e.g., page 9, line 22 to page 14, line 14), WO2007/066103 (see, e.g., page 9, line 22 to page 14, line 16), WO2007/060404 (see, e.g., 5, line 4 to page 7, line 25), WO 2006/090169(see, e.g., page 4, lines 1-25), WO 2006/090167 (see, e.g., page 3, line33 to page 6, line 23), WO 2008/115974 (see, e.g., page 4, paragraph[0012] to page 127, paragraph [0257]), WO 2009/052145 (see, e.g., page5, paragraph [0015] to page 81, paragraph [0082]), WO 2010/006072 (see,e.g., page 28, line 1 to page 34, line 1), WO 2007/044698 (see, e.g.,page 3, paragraph [0010] to the bottom of page 7), WO 2007/044813 (see,e.g., page 3, paragraph [0010] to the middle of page 7), WO 2007/044729(see, e.g., page 3, paragraph [0010] to the bottom of page 10), WO2007/129161 (see, e.g., page 2, line 10 to page 9, line 19), WO2006/046031 (see, e.g., page 2, line 15 to page 4, line 12), WO2003/072557 (see, e.g., page 1, line 4 to page 2, line 27), WO2004/048365 (see, e.g., page 1, line 4 to page 4, line 17), WO2004/078754 (see, e.g., page 1, line 4 to page 2, line 21), WO2004/096797 (see, e.g., page 1, line 4 to page 2, line 34), WO2005/021519 (see, e.g., page 1, line 4 to page 4, line 17) or US2007/112005 (see, e.g., page 2, paragraph [0012] to page 22, paragraph[0065]), each of which is incorporated by reference herein in itsentirety.

6.3 Methods for Making TOR Kinase Inhibitors

The TOR kinase inhibitors can be obtained via standard, well-knownsynthetic methodology, see e.g., March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992. Starting materialsuseful for preparing compounds of formula (III) and intermediatestherefore, are commercially available or can be prepared fromcommercially available materials using known synthetic methods andreagents.

Particular methods for preparing compounds of formula (I) are disclosedin U.S. application Ser. No. 11/975,652, filed Oct. 18, 2007,incorporated by reference herein in its entirety. Particular methods forpreparing compounds of formula (II) are disclosed in U.S. applicationSer. No. 11/975,657, filed Oct. 18, 2007, incorporated by referenceherein in its entirety. Particular methods for preparing compounds offormula (III) and (IV) are disclosed in U.S. application Ser. No.12/605,791, filed Oct. 26, 2009, incorporated by reference herein in itsentirety.

6.4 Methods of Use

Without being limited by theory, it is believed that LKB1 plays animportant role in the nutrient sensing arm of the mTOR pathway. Inparticular, it is believed that LKB1 is a negative regulator of the mTORpathway under stress conditions, such as hypoxia and low glucose. LKB1suppresses mTOR activity via its downsteam kinase, AMP-activated proteinkinase (AMPK). In response to energy stress, LKB1 phosphorylates theAMPK catalytic subunit at T172 and this phosphorylation is essential foractivation of AMPK. Activated AMPK phosphorylates TSC2 and raptor, andsuppresses mTOR activity [Shackelford D B and Shaw J S, Nat. Rev Cancer9:563 (2009)]. Therefore, phosphorylation or activity of AMPK can beused as a marker for LKB1 status. In basal conditions, it is believedthat loss of LKB1 and/or AMPK can result in activation of the mTORpathway. In cancer cells, under stress conditions, it is believed thatthe LKB1/AMPK pathway may actually play a protective role by causingcells to slow down their proliferation and thus evade apoptosis inducedby the stress condition. However, it is believed that in LKB1 mutantcancer cells (e.g., cells harboring a LKB1 gene mutation resulting in adecrease in LKB1 mRNA expression, a decrease in LKB1 protein productionor a non-functional LKB1 protein), in the absence of the negative signalto mTOR, the cancer cells continue to proliferate and undergo metaboliccatastrophe. Accordingly, without being limited by theory, it isbelieved that TOR kinase inhibitors by their effects on cell metabolismcause a stress response in cancer cells and in LKB1 mutant cancer cells,and in the absence of a negative signal to slow the growth of the cells,result in cell death.

Provided herein are methods for treating or preventing cancer, forexample non-small cell lung carcinoma or cervical cancer, or treating atumor syndrome, for example Peutz-Jeghers Syndrome, comprisingadministering an effective amount of a TOR kinase inhibitor to a patienthaving cancer, for example non-small cell lung carcinoma or cervicalcancer, or a tumor syndrome, for example Peutz-Jeghers Syndrome,characterized by loss of LKB1 and/or AMPK gene or protein loss ormutation, relative to that of a control patient or wild type.

Provided herein are methods for treating or preventing a cancer, forexample non-small cell lung carcinoma or cervical cancer, or treating atumor syndrome, for example Peutz-Jeghers Syndrome, comprisingadministering an effective amount of a TOR kinase inhibitor to a patienthaving a cancer or a tumor syndrome characterized by a reduced level ofphospho-AMPK (pAMPK) protein or AMPK activity, relative to that of acontrol patient or wild type. In one embodiment, the pAMPK is pAMPKT172.

Further provided herein are methods for treating or preventing cancer,for example non-small cell lung carcinoma or cervical cancer, comprisingscreening a patient's cancer for the presence of LKB1 and/or AMPK geneor protein loss or mutation, relative to that of a control patient orwild type, and administering an effective amount of a TOR kinaseinhibitor to the patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, characterized by the LKB1 and/or AMPK geneor protein loss or mutation.

Further provided herein are methods for treating or preventing cancer,for example non-small cell lung carcinoma or cervical cancer, comprisingscreening a patient's cancer for the presence of a reduced level ofpAMPK protein or AMPK activity relative to that of a control patient orwild type, and administering an effective amount of a TOR kinaseinhibitor to the patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, characterized by a reduced level of pAMPKprotein or AMPK activity. In one embodiment, the pAMPK is pAMPK T172.

Further provided herein are methods for detecting LKB1 gene or proteinloss or mutation in a patient's (“test patient”) cancer, for examplenon-small cell lung carcinoma or cervical cancer, comprising: obtaininga biological sample from the test patient's cancer; measuring one ormore of the level of LKB1 mRNA expression, the level of LKB1 proteinexpression, determining the methylation status of the LKB1 gene orotherwise identifying the presence of LKB1 gene or protein loss ormutation (e.g., by cDNA or direct cDNA or exon DNA sequencing or SNPanalysis or multiple ligation probe amplification (MLPA) to identifycopy number loss or immunohistochemistry (IHC), immunofluorescence (IF),or Western Blot to determine loss of protein); and comparing saidmeasurement with a control measurement from a patient's (“controlpatient”) cancer which is not characterized by a LKB1 gene or proteinloss or mutation (wild type); wherein a change in LKB1 mRNA expression,LKB1 protein expression, LKB1 mRNA structure, LKB1 gene methylationstatus and/or LKB1 protein structure in the biological sample from thetest patient, relative to that of a control patient or wild-type,indicates the presence of LKB1 gene or protein loss or mutation in thetest patient's cancer.

Further provided herein are methods for detecting AMPK gene or proteinloss or mutation in a patient's (“test patient”) cancer, for examplenon-small cell lung carcinoma or cervical cancer, comprising: obtaininga biological sample from the test patient's cancer; measuring one ormore of the level of AMPK mRNA expression, the level of AMPK proteinexpression, determining the methylation status of the AMPK gene orotherwise identifying the presence of AMPK gene or protein loss ormutation (e.g., by cDNA or direct cDNA or exon DNA sequencing or SNPanalysis or multiple ligation probe amplification (MLPA) to identifycopy number loss or immunohistochemistry (IHC), immunofluorescence (IF),or Western Blot to determine loss of protein); and comparing saidmeasurement with a control measurement from a patient's (“controlpatient”) cancer which is not characterized by a AMPK gene or proteinloss or mutation (wild type); wherein a change in AMPK mRNA expression,AMPK protein expression, AMPK mRNA structure, AMPK gene methylationstatus and/or AMPK protein structure in the biological sample from thetest patient, relative to that of a control patient or wild-type,indicates the presence of LKB1 gene or protein loss or mutation in thetest patient's cancer.

Further provided herein are methods for detecting a reduced level ofpAMPK protein and/or AMPK activity in a patient's (“test patient”)cancer, for example non-small cell lung carcinoma or cervical cancer,comprising: obtaining a biological sample from the test patient'scancer; measuring one or more of the level of, pAMPK protein expression,the level of AMPK activity, or otherwise measuring the level of pAMPKprotein (e.g., immunohistochemistry (IHC), immunofluorescence (IF), orWestern Blot to determine the amount of pAMPK protein or the amount ofphosphorylation of AMPK at specific sites, for example at the T172site), and/or the level of AMPK activity (e.g. AMPK kinase assay, seeSanders et al. Biochem. J. 403:139-148 (2007)); and comparing saidmeasurement with a control measurement from a patient's (“controlpatient”) cancer which is not characterized by a reduced level of pAMPKprotein and/or AMPK activity (wild type); wherein a lower level of pAMPKprotein and/or AMPK activity in the biological sample from the testpatient, relative to that of a control patient or wild type, indicatesthe presence of a reduced level of pAMPK protein and/or AMPK activity inthe test patient's cancer. In one embodiment, the pAMPK is pAMPK T172.

Further provided herein are methods for predicting the likelihood of apatient (“test patient”) having cancer, for example non-small cell lungcarcinoma or cervical cancer, being responsive to TOR kinase inhibitortherapy, comprising: obtaining a biological sample from the testpatient's cancer; measuring one or more of the level of LKB1 mRNAexpression, the level of LKB1 protein expression, determining themethylation status of the LKB1 gene or otherwise identifying thepresence of LKB1 gene or protein loss or mutation (e.g., by direct cDNAor exon DNA sequencing or SNP analysis or multiple ligation probeamplification (MLPA) to identify copy number loss orimmunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient's (“control patient”) cancer which isnot characterized by a LKB1 gene or protein loss or mutation; wherein achange in LKB1 mRNA expression, LKB1 protein expression, LKB1 mRNAstructure, LKB1 gene methylation status and/or LKB1 protein structure inthe biological sample from the test patient, relative to that of acontrol patient or wild-type, predicts an increased likelihood that TORkinase inhibitor therapy will treat said cancer, for example non-smallcell lung carcinoma or cervical cancer.

Further provided herein are methods for predicting the likelihood of apatient (“test patient”) having cancer, for example non-small cell lungcarcinoma or cervical cancer, being responsive to TOR kinase inhibitortherapy, comprising: obtaining a biological sample from the testpatient's cancer; measuring one or more of the level of AMPK mRNAexpression, the level of AMPK protein expression, determining themethylation status of the AMPK gene or otherwise identifying thepresence of AMPK gene or protein loss or mutation (e.g., by direct cDNAor exon DNA sequencing or SNP analysis or multiple ligation probeamplification (MLPA) to identify copy number loss orimmunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient's (“control patient”) cancer which isnot characterized by loss of AMPK gene or protein loss or mutation;wherein a change in AMPK mRNA expression, AMPK protein expression, AMPKmRNA structure, AMPK gene methylation and/or AMPK protein structure inthe biological sample from the test patient, relative to that of acontrol patient or wild-type, predicts an increased likelihood that TORkinase inhibitor therapy will treat said cancer, for example non-smallcell lung carcinoma or cervical cancer.

Further provided herein are methods for predicting the likelihood of apatient (“test patient”) having cancer, for example non-small cell lungcarcinoma or cervical cancer, being responsive to TOR kinase inhibitortherapy, comprising: obtaining a biological sample from the testpatient's cancer; measuring one or more of the level of pAMPK proteinexpression, the level of AMPK activity, or otherwise measuring the levelof pAMPK protein (e.g., immunohistochemistry (IHC), immunofluorescence(IF), or Western Blot to determine the amount of pAMPK protein, or theamount of phosphorylation of AMPK at specific sites, for example at theT172 site), and/or the level of AMPK activity (e.g. AMPK kinase assay,see Sanders et al. Biochem. J. 403:139-148 (2007)); and comparing saidmeasurement with a control measurement from a patient's (“controlpatient”) cancer which is not characterized by a reduced level of pAMPKprotein and/or AMPK activity (wild type); wherein a lower level of pAMPKprotein and/or AMPK activity in the biological sample from the testpatient, relative to that of a control patient or wild type, predicts anincreased likelihood that TOR kinase inhibitor therapy will treat saidcancer, for example non-small cell lung carcinoma or cervical cancer. Inone embodiment, the pAMPK is pAMPK T172.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, with a TOR kinase inhibitor, comprising:screening said patient's cancer for the presence of LKB1 and/or AMPKgene or protein loss or mutation, relative to that of a control patientor wild type, wherein the presence of said LKB1 and/or AMPK gene orprotein loss or mutation in the patient's cancer is predictive oftherapeutic efficacy of treatment with a TOR kinase inhibitor.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having cancer, for example non-small cell lungcarcinoma or cervical cancer, with a TOR kinase inhibitor, comprising:screening said patient's cancer for the presence of a reduced level ofpAMPK protein and/or AMPK activity, relative to that of a controlpatient or wild type, wherein the presence of said reduced level ofpAMPK protein and/or AMPK activity in the patient's cancer is predictiveof therapeutic efficacy of treatment with a TOR kinase inhibitor. In oneembodiment, the pAMPK is pAMPK T172.

Further provided herein are methods for treating a tumor syndrome, forexample Peutz-Jeghers Syndrome, comprising screening the patient for thepresence of a LKB11 and/or AMPK gene or protein loss or mutation,relative to that of a control patient or wild type, and administering aneffective amount of a TOR kinase inhibitor to the patient having theLKB1 and/or AMPK gene or protein loss or mutation.

Further provided herein are methods for treating a tumor syndrome, forexample Peutz-Jeghers Syndrome, comprising screening the patient for thepresence of a reduced level of pAMPK protein and/or AMPK activity,relative to that of a control patient or wild type, and administering aneffective amount of a TOR kinase inhibitor to the patient having thereduced level of pAMPK protein and/or AMPK activity. In one embodiment,the pAMPK is pAMPK T172.

Further provided herein are methods for detecting LKB1 gene or proteinloss or mutation in a patient (“test patient”) having a tumor syndrome,for example, Peutz-Jeghers Syndrome, comprising: obtaining a biologicalsample from the test patient; measuring one or more of the level of LKB1mRNA expression, the level of LKB1 protein expression, determining themethylation status of the LKB1 gene or otherwise identifying thepresence of gene or protein loss or mutation (e.g., by direct cDNA orexon DNA sequencing or SNP analysis or multiple ligation probeamplification (MLPA) to identify copy number loss, orimmunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient (“control patient”) without the LKB1gene or protein loss or mutation (wild type); wherein a change in LKB1mRNA expression, LKB1 protein expression, LKB1 mRNA structure, LKB1 genemethylation status and/or LKB1 protein structure in the biologicalsample from the test patient, relative to that of a control patient orwild-type, indicates the presence of LKB1 gene or protein loss ormutation in said the test patient. Examples of biological samplesinclude but are not limited to, tissue samples, blood, saliva, hair,disease tissue samples, buccal smears or tumor samples.

Further provided herein are methods for detecting AMPK gene or proteinloss or mutation in a patient (“test patient”) having a tumor syndrome,for example, Peutz-Jeghers Syndrome, comprising: obtaining a biologicalsample from the test patient; measuring one or more of the level of AMPKmRNA expression, the level of AMPK protein expression, determining themethylation status of the AMPK gene or otherwise identifying thepresence of gene or protein loss or mutation (e.g., by direct cDNA orexon DNA sequencing or SNP analysis or multiple ligation probeamplification (MLPA) to identify copy number loss, orimmunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine loss of protein); and comparing said measurement with acontrol measurement from a patient (“control patient”) without the AMPKgene or protein loss or mutation (wild type); wherein a change in AMPKmRNA expression, AMPK protein expression, AMPK mRNA structure, AMPK genemethylation status and/or AMPK protein structure in the biologicalsample from the test patient, relative to that of a control patient orwild-type, indicates the presence of AMPK gene or protein loss ormutation in the test patient. Examples of biological samples include butare not limited to, tissue samples, blood, saliva, hair, disease tissuesamples, buccal smears or tumor samples.

Further provided herein are methods for detecting a reduced level ofpAMPK protein and/or AMPK activity in a patient (“test patient”) havinga tumor syndrome, for example, Peutz-Jeghers Syndrome, comprising:obtaining a biological sample from the test patient; measuring one ormore of the level of, pAMPK protein expression, the level of AMPKactivity, or otherwise measuring the level of pAMPK protein (e.g.,immunohistochemistry (IHC), immunofluorescence (IF), or Western Blot todetermine the amount of pAMPK protein or the amount of phosphorylationof AMPK at specific sites, for example at the T172 site), and/or thelevel of AMPK activity (e.g. AMPK kinase assay, see Sanders et al.Biochem. J. 403:139-148 (2007)); and comparing said measurement with acontrol measurement from a patient's (“control patient”) without areduced level of pAMPK protein and/or AMPK activity (wild type); whereina lower level of pAMPK protein and/or AMPK activity in the biologicalsample from the test patient, relative to that of a control patient orwild type, indicates the presence of a reduced level of pAMPK proteinand/or AMPK activity in the test patient. In one embodiment, the pAMPKis pAMPK T172. Examples of biological samples include but are notlimited to, tissue samples, blood, saliva, hair, disease tissue samples,buccal smears or tumor samples.

Further provided herein are methods for predicting the likelihood of apatient having a tumor syndrome, for example Peutz-Jeghers Syndrome,being responsive to TOR kinase inhibitor therapy, comprising screeningsaid patient for the presence of LKB1 and/or AMPK gene or protein lossor mutation, relative to that of a control patient or wild type, whereinthe presence of LKB1 and/or AMPK gene or protein loss or mutationpredicts an increased likelihood that TOR kinase inhibitor therapy willtreat said tumor syndrome.

Further provided herein are methods for predicting the likelihood of apatient having a tumor syndrome, for example Peutz-Jeghers Syndrome,being responsive to TOR kinase inhibitor therapy, comprising screeningsaid patient for the presence of a reduced level of pAMPK protein and/orAMPK activity, relative to that of a control patient or wild type,wherein the presence of a reduced level of pAMPK protein and/or AMPKactivity predicts an increased likelihood that TOR kinase inhibitortherapy will treat said tumor syndrome. In one embodiment, the pAMPK ispAMPK T172.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having a tumor syndrome, for examplePeutz-Jeghers Syndrome, with a TOR kinase inhibitor, comprisingscreening said patient for the presence of LKB1 and/or AMPK gene orprotein loss or mutation, relative to that of a control patient or wildtype, wherein the presence of LKB1 and/or AMPK gene or protein loss ormutation in the patient is predictive of therapeutic efficacy oftreatment with a TOR kinase inhibitor.

Further provided herein are methods for predicting therapeutic efficacyof treatment of a patient having a tumor syndrome, for examplePeutz-Jeghers Syndrome, with a TOR kinase inhibitor, comprisingscreening said patient for the presence of a reduced level of pAMPKprotein and/or AMPK activity, relative to that of a control patient orwild type, wherein the presence of a reduced level of pAMPK proteinand/or AMPK activity in the patient is predictive of therapeuticefficacy of treatment with a TOR kinase inhibitor. In one embodiment,the pAMPK is pAMPK T172.

Further provided herein are methods for treating or preventing cancer,for example non-small cell lung carcinoma or cervical cancer, ortreating a tumor syndrome, for example Peutz-Jeghers Syndrome,comprising administering an effective amount of a TOR kinase inhibitorand an effective amount of one or more agents that modulate AMP levels,glucose uptake, metabolism or a stress response to a patient havingcancer, for example non-small cell lung carcinoma or cervical cancer, ora tumor syndrome, for example Peutz-Jeghers Syndrome.

Further provided herein are kits comprising one or more containersfilled with a TOR kinase inhibitor or a pharmaceutical compositionthereof, reagents for detecting LKB1 gene or protein loss or mutation,or AMPK gene or protein loss or mutation, or both, in a patient's canceror in a patient having a tumor syndrome, and instructions for detectingLKB1 gene or protein loss or mutation, or AMPK gene or protein loss ormutation, or both, in a patient's cancer or in a patient having a tumorsyndrome. In one embodiment, the kit further comprises instructions foradministering a TOR kinase inhibitor or a pharmaceutical compositionthereof to a patient in need thereof.

Further provided herein are kits comprising one or more containersfilled with a TOR kinase inhibitor or a pharmaceutical compositionthereof, reagents for detecting a reduced level of pAMPK protein and/orAMPK activity in a patient's cancer or in a patient having a tumorsyndrome, and instructions for detecting a reduced level of pAMPKprotein and/or AMPK activity in a patient's cancer or in a patienthaving a tumor syndrome. In one embodiment, the kit further comprisesinstructions for administering a TOR kinase inhibitor or apharmaceutical composition thereof to a patient in need thereof.

In one embodiment, the LKB1 gene mutation or loss results in a decreasein LKB1 mRNA expression (e.g., relative to wild-type). In anotherembodiment, the LKB1 gene mutation or loss results in a change in LKB1mRNA structure (e.g., relative to wild-type). In another embodiment, theLKB1 gene mutation or loss results in a decrease in LKB1 proteinproduction (e.g., relative to wild-type). In another embodiment, theLKB1 gene mutation or loss results in a change in LKB1 protein structure(e.g., relative to wild-type). Types of gene mutations contemplatedinclude mutations of the LKB1 DNA sequence in which the number of basesis altered, categorized as insertion or deletion mutations (frameshiftmutations), and mutations of the DNA that change one base into another,categorized as missense mutations, which are subdivided into the classesof transitions (one purine to another purine, or one pyrimidine toanother pyrimidine) and transversions (a purine to a pyrimidine, or apyrimidine to a purine) and nonsense mutations, wherein a codon encodingan amino acid is changed to a stop codon, thus resulting in truncatedprotein.

In one embodiment, the LKB1 gene mutation or loss results in a decreasein AMPK phosphorylation (e.g. relative to wild type). In anotherembodiment, the LKB1 gene mutation or loss results in a decrease in AMPKphosphorylation at T172. (e.g. relative to wild type). In anotherembodiment, the LKB1 gene mutation or loss results in a decrease in thelevel pAMPK protein (e.g. relative to wild type). In another embodiment,the LKB1 gene mutation or loss results in a decrease in AMPK activity(i.e. kinase activity) (e.g. relative to wild type).

In one embodiment, the AMPK gene mutation or loss results in a decreasein AMPK mRNA expression (e.g., relative to wild-type). In anotherembodiment, the AMPK gene mutation or loss results in a change in AMPKmRNA structure (e.g., relative to wild-type). In another embodiment, theAMPK gene mutation or loss results in a decrease in AMPK proteinproduction (e.g., relative to wild-type). In another embodiment, theAMPK gene mutation or loss results in a change in AMPK protein structure(e.g., relative to wild-type). Types of gene mutations contemplatedinclude mutations of the AMPK DNA sequence in which the number of basesis altered, categorized as insertion or deletion mutations (frameshiftmutations), and mutations of the DNA that change one base into another,categorized as missense mutations, which are subdivided into the classesof transitions (one purine to another purine, or one pyrimidine toanother pyrimidine) and transversions (a purine to a pyrimidine, or apyrimidine to a purine) and nonsense mutations, wherein a codon encodingan amino acid is changed to a stop codon, thus resulting in truncatedprotein.

In certain embodiments, the cancer, for example non-small cell lungcarcinoma or cervical cancer, or the tumor syndrome, for examplePeutz-Jeghers Syndrome, results directly or indirectly from LKB1 and/orAMPK gene or protein loss or mutation, relative to that of a controlpatient or wild type.

In one embodiment, the LKB1 and/or AMPK gene mutation is a somaticmutation.

In one embodiment, a patient or a patient's cancer is screened for LKB1and/or AMPK gene or protein loss or mutation by obtaining a biologicalsample from said patient or said patient's cancer, and analyzing saidsample ex vivo. In certain embodiments, the ex vivo analysis isperformed by LKB1 gene direct cDNA or exon DNA sequencing, SNP analysisor multiple ligation probe amplification (MLPA) (e.g., to identify copynumber loss) or immunohistochemistry (IHC), immunofluorescence (IF), orWestern Blot (e.g., to determine loss of protein). In certainembodiments, the ex vivo analysis is performed by AMPK gene direct cDNAor exon DNA sequencing, SNP analysis or multiple ligation probeamplification (MLPA) (e.g., to identify copy number loss) orimmunohistochemistry (IHC) or Western Blot (e.g., to determine loss ofprotein). In another embodiment, a patient or a patient's cancer isscreened for a reduced level of pAMPK protein and/or AMPK activity byobtaining a biological sample from said patient or said patient'scancer, and analyzing said sample ex vivo. In certain embodiments, theex vivo analysis is performed by immunohistochemistry (IHC),immunofluorescence (IF), or Western Blot (e.g. to determine the amountof pAMPK protein or the amount of phosphorylation of AMPK at specificsites, for example at the T172 site), or by a AMPK kinase assay (e.g. todetermine the level of AMPK activity).

A TOR kinase inhibitor can be combined with other pharmacologicallyactive compounds (“second active agents”) in methods and compositionsdescribed herein. It is believed that certain combinations may work inthe treatment of particular types of diseases or disorders, andconditions and symptoms associated with such diseases or disorders. ATOR kinase inhibitor can also work to alleviate adverse effectsassociated with certain second active agents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions described herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of second active agents include, but are not limited to, agentsthat modulate AMP levels (e.g., an AMP activator), glucose uptake,metabolism or a stress response. In one embodiment, the second activeagent is 2-deoxyglucose. In one embodiment, the second active agent ismetformin. In one embodiment, the second active agent is phenformin. Inanother embodiment, the second active agent is pemetrexed (e.g.,ALIMTA®).

Administration of a TOR kinase inhibitor and one or more second activeagents to a patient can occur simultaneously or sequentially by the sameor different routes of administration. The suitability of a particularroute of administration employed for a particular active agent willdepend on the active agent itself (e.g., whether it can be administeredorally without decomposing prior to entering the blood stream) and thedisease being treated. A preferred route of administration for a TORkinase inhibitor is oral. Preferred routes of administration for thesecond active agents or ingredients of the invention are known to thoseof ordinary skill in the art. See, e.g., Physicians' Desk Reference,1755-1760 (56th ed., 2002).

In one embodiment, a second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of a TOR kinase inhibitor and any optional additionalactive agents concurrently administered to the patient.

Further provided herein are methods of reducing, treating and/orpreventing adverse or undesired effects associated with conventionaltherapy including, but not limited to, surgery, chemotherapy, radiationtherapy, hormonal therapy, biological therapy and immunotherapy. TORkinase inhibitors and other active ingredients can be administered to apatient prior to, during, or after the occurrence of the adverse effectassociated with conventional therapy.

6.5 Pharmaceutical Compositions and Routes of Administration

Provided herein are compositions comprising an effective amount of a TORkinase inhibitor and compositions comprising an effective amount of aTOR kinase inhibitor and a pharmaceutically acceptable carrier orvehicle. In some embodiments, the pharmaceutical composition describedherein are suitable for oral, parenteral, mucosal, transdermal ortopical administration.

The TOR kinase inhibitors can be administered to a patient orally orparenterally in the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g., sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the TOR kinase inhibitor in the pharmaceuticalcomposition may be at a level that will exercise the desired effect; forexample, about 0.005 mg/kg of a patient's body weight to about 10 mg/kgof a patient's body weight in unit dosage for both oral and parenteraladministration.

The dose of a TOR kinase inhibitor to be administered to a patient israther widely variable and can be patient to the judgment of ahealth-care practitioner. In general, the TOR kinase inhibitors can beadministered one to four times a day in a dose of about 0.005 mg/kg of apatient's body weight to about 10 mg/kg of a patient's body weight in apatient, but the above dosage may be properly varied depending on theage, body weight and medical condition of the patient and the type ofadministration. In one embodiment, the dose is about 0.01 mg/kg of apatient's body weight to about 5 mg/kg of a patient's body weight, about0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient'sbody weight, about 0.1 mg/kg of a patient's body weight to about 0.75mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's bodyweight to about 0.5 mg/kg of a patient's body weight. In one embodiment,one dose is given per day. In any given case, the amount of the TORkinase inhibitor administered will depend on such factors as thesolubility of the active component, the formulation used and the routeof administration.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about55 mg/day or about 18 mg/day to about 37 mg/day of a TOR kinaseinhibitor to a patient in need thereof.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day toabout 800 mg/day or about 600 mg/day to about 800 mg/day of a TOR kinaseinhibitor to a patient in need thereof. In a particular embodiment, themethods disclosed herein comprise the administration of 400 mg/day, 600mg/day or 800 mg/day of a TOR kinase inhibitor to a patient in needthereof.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and about 2000 mg, about 1 mg and 200 mg,about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250mg and about 1000 mg, or about 500 mg and about 1000 mg of a TOR kinaseinhibitor.

In a particular embodiment, provided herein are unit dosage formulationcomprising about 100 mg or 400 mg of a TOR kinase inhibitor.

In another embodiment, provided herein are unit dosage formulations thatcomprise 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg,70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg,500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a TOR kinaseinhibitor.

A TOR kinase inhibitor can be administered once, twice, three, four ormore times daily.

A TOR kinase inhibitor can be administered orally for reasons ofconvenience. In one embodiment, when administered orally, a TOR kinaseinhibitor is administered with a meal and water. In another embodiment,the TOR kinase inhibitor is dispersed in water or juice (e.g., applejuice or orange juice) and administered orally as a suspension. Inanother embodiment, when administered orally, a TOR kinase inhibitor isadministered in a fasted state.

The TOR kinase inhibitor can also be administered intradermally,intramuscularly, intraperitoneally, percutaneously, intravenously,subcutaneously, intranasally, epidurally, sublingually, intracerebrally,intravaginally, transdermally, rectally, mucosally, by inhalation, ortopically to the ears, nose, eyes, or skin. The mode of administrationis left to the discretion of the health-care practitioner, and candepend in-part upon the site of the medical condition.

In one embodiment, provided herein are capsules containing a TOR kinaseinhibitor without an additional carrier, excipient or vehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a TOR kinase inhibitor and a pharmaceuticallyacceptable carrier or vehicle, wherein a pharmaceutically acceptablecarrier or vehicle can comprise an excipient, diluent, or a mixturethereof. In a further embodiment, provided herein are compositionscomprising an effective amount of a TOR kinase inhibitor, and apharmaceutically acceptable carrier or vehicle, and one or more agentsthat modulate AMP levels, glucose uptake, metabolism or a stressresponse. In one embodiment, the composition is a pharmaceuticalcomposition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a TOR kinase inhibitorwith a suitable carrier or diluent and filling the proper amount of themixture in capsules. The usual carriers and diluents include, but arenot limited to, inert powdered substances such as starch of manydifferent kinds, powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. In one embodiment, the pharmaceutical composition islactose-free. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a TOR kinase inhibitor as asuppository, typical bases can be used. Cocoa butter is a traditionalsuppository base, which can be modified by addition of waxes to raiseits melting point slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the TOR kinase inhibitor can be delayed or prolonged byproper formulation. For example, a slowly soluble pellet of the TORkinase inhibitor can be prepared and incorporated in a tablet orcapsule, or as a slow-release implantable device. The technique alsoincludes making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules canbe coated with a film that resists dissolution for a predictable periodof time. Even the parenteral preparations can be made long-acting, bydissolving or suspending the TOR kinase inhibitor in oily or emulsifiedvehicles that allow it to disperse slowly in the serum.

7. EXAMPLES 7.1 Biological Examples

7.1.1 Biochemical Assays

TOR HTR-FRET Assay. The following is an example of an assay that can beused to determine the TOR kinase inhibitory activity of a test compound.TORKi were dissolved in DMSO and prepared as 10 mM stocks and dilutedappropriately for the experiments.

Reagents were prepared as follows:

“Simple TOR buffer” (used to dilute high glycerol TOR fraction): 10 mMTris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogenrecombinant TOR enzyme (cat #PR8683A) was diluted in this buffer to anassay concentration of 0.200 μg/mL.

ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl₂, 50 mM Hepes, pH7.4, 50 mM β-GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT, and 3.5μg/mL GST-p70S6.

Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100,0.01% BSA, 0.1 mM EDTA, 12.7 μg/mL Cy5-αGST Amersham (Cat #PA92002V), 9ng/mL α-phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L),627 ng/mL α-mouse Lance Eu (Perkin Elmer Cat #AD0077).

To 20 μL of the Simple TOR buffer is added 0.5 μL of test compound inDMSO. To initiate the reaction 5 μL of ATP/Substrate solution was addedto 20 μL of the Simple TOR buffer solution (control) and to the compoundsolution prepared above. The assay was stopped after 60 min by adding 5μL of a 60 mM EDTA solution; 10 μL of detection reagent solution wasthen added and the mixture was allowed to sit for at least 2 hoursbefore reading on a Perkin-Elmer Envision Microplate Reader set todetect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520nm).

TORKi were tested in the TOR HTR-FRET assay and were found to haveactivity therein, with certain compounds having an IC₅₀ below 10 μM inthe assay, with some compounds having an IC₅₀ between and 0.005 nM and250 nM, others having an IC₅₀ between and 250 nM and 500 nM, othershaving an IC₅₀ between 500 nM and 1 μM, and others having an IC₅₀between 1 μM and 10 μM.

DNA-PK assay. DNA-PK assays were performed using the procedures suppliedin the Promega DNA-PK assay kit (catalog #V7870). DNA-PK enzyme waspurchased from Promega (Promega cat #V5811).

Selected TORKi have, or are expected to have, an IC₅₀ below 10 μM inthis assay, with some TORKi having an IC₅₀ below 1 μM, and others havingan IC₅₀ below 0.10 μM

7.1.2 Cell Based Assays

Materials and Methods. Cell lines and cell culture: Human lung cancercell lines were purchased from American Type Culture Collection (ATCC)and maintained in RPMI 1640 plus 10% bovine calf serum (FCS) or specialculture medium recommended by ATCC. The non-small cell lung cancer cells(NSCLC cancer panel) include the following cell lines NCI-H460,NCI-H838, NCI-H1792, NCI-H520, NCI-H1993, NCI-H1944, NCI-H1975,NCI-H1395, A549, NCI-H2122, NCI-H1703, NCI-H1299, NCI-H647, NCI-H358,SK-LU-1, NCI-H1734, NCI-H1693, NCI-H226, NCI-H23, NCI-H2030, NCI-H1755,Calu-6, Calu-1, SW1573, NCI-H2009, NCI-H441, HOP92, NCI-H2110, NCI-H727,NCI-H1568, Calu-3, NCI-H2228, NCI-H2444, NCI-H1563, NCI-H1650,NCI-H1437, NCI-H650, NCI-H1838, NCI-H2291, NCI-H28 and NCI-H596.Additional cell lines that TOR kinase inhibitors can be tested againstinclude HT-3, HeLaSF, Hela S3, SKG-IIIa, SiHa, MS751, BOKU, C-33-A,C-4-II, Ca-Ski, DoTc2-4510, ME-180, OMC-1. SW756, and TC-YIK.

Cell viability assay. A representative TOR kinase inhibitor (“Compound1”) was used in the following biochemical assay. Cell viability wasassessed using the Cell Titer-Glo Luminescent Cell Viability fromPromega. The assay is a homogenous method of determining the number ofviable cells in culture based on quantitation of the adenosinetriphosphate (ATP) present, an indicator of metabolically active cells.The homogenous assay procedure involves adding the single reagent(CellTiter-Glo Reagent) directly to cells cultured in serum-supplementedmedium. Cells were plated into a 96-well flat bottom plate (CostarCatalog Number 33595) at densities that were previously optimized foreach cell line. The cells were incubated overnight in 5% CO₂ at 37° C.The following day, compound dilutions were prepared from a 30 mM stock.Compound 1 was first diluted in 100% DMSO and then diluted 1:50 intogrowth media. Next, Compound 1 was added to the appropriate well at adilution of 1:10 (i.e., ten microliters (10 μL) of the diluted Compound1 was added to 90 μL of culture media in each well). The final dilutionof Compound 1 was 1:500, which yielded a final DMSO concentration of0.2% in each well. All concentrations were performed in triplicate. Thecells were incubated with Compound 1 in 5% CO₂ at 37° C. for 3 days.After a 3-day incubation period, 100 μL of CellTiter-Glo reagent wasadded to each well for 2 minutes with shaking and further incubated for10 minutes (no shaking) at room temperature to stabilize the signal. Theluminescence was measured on the VICTOR X2 multilabel plate reader. Thepercent growth inhibition was calculated using the DMSO control responseas 100% cell growth in the same plate. The average values fromtriplicates were plotted to obtain IC₅₀ values using software XLfit fromIDBS. The formula used for determining IC₅₀ in XLfit was model number205, which utilizes a 4 Parameter Logistic Model or SigmoidalDose-Response Model to calculate the IC₅₀ values. All IC₅₀ values arereported as an average from either two or three independent experiments.

LKB1 protein expression analysis. The whole lysates were prepared inradio-immunoprecipitation assay buffer [10 mmol/L Tris (pH 7.4), 100mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L EGTA, 1 mmol/L NaF, 20 mmol/LNa₄P₂O₇, 2 mmol/L Na₃CO₄, 0.1% SDS, 0.5% sodium deoxycholate, 1% TritonX-100, 10% glycerol] containing protease inhibitors. Cell lysatescontaining 50 μg of protein were fractionated on 4-12% Nu-PAGE® gels andtransferred to nitrocellulose membrane. The membrane was incubated withanti-LKB1 antibody (#3050, Cell Signaling Technology) overnight at 4° C.The membrane was washed three times with PBS+0.1% Tween beforeincubation with anti-rabbit secondary antibody for 1 hour at roomtemperature. The membrane was washed three times with PBS+0.1% Tweenbefore scanning on the LI-COR Odyssey® scanner at 700 nm and 800 nmwavelengths.

Statistical Analysis. The correlation between IC₅₀ values acrossdifferent mutation status were assessed using either Wilcoxon test,where the number of groups equals to 2, or Kruskal-Wallis test, wherethe number of groups is bigger than 2. P value <0.05 is considered assignificant correlation.

Phospho AMPK T172 protein expression analysis. The whole lysates wereprepared in radio-immunoprecipitation assay buffer [10 mmol/L Tris (pH7.4), 100 mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L EGTA, 1 mmol/L NaF, 20mmol/L Na₄P₂O₇, 2 mmol/L Na₃CO₄, 0.1% SDS, 0.5% sodium deoxycholate, 1%Triton X-100, 10% glycerol] containing protease inhibitors. Cell lysatescontaining 50 μg of protein were fractionated on 4-12% Nu-PAGE® gels andtransferred to nitrocellulose membrane. The membrane was incubated withanti-phospho-AMPK T172 (#4188, Cell Signaling Technology, Danvers,Mass.) anti-AMPK alpha (#2793, Cell Signaling Technology, Danvers,Mass.) and anti β-actin (#1978, Sigma-Aldrich, St. Louis, Mo.) overnightat 4° C. The membrane was washed three times with PBS+0.1% Tween beforeincubation with anti-rabbit secondary antibody for 1 hour at roomtemperature. The membrane was washed three times with PBS+0.1% Tweenbefore scanning on the LI-COR Odyssey® scanner at 700 nm and 800 nmwavelengths. The levels of pAMPK T172, AMPK and actin were quantitatedusing LI-COR Odyssey® software. The ratio of pAMPK T172 vs. actin(pAMPK/actin) was applied to Wilcoxon statistical analysis.

Statistical analysis. The correlation between phospho-AMPK T172expression level and LKB1 protein expression level status was assessedusing Wilcoxon test. LKB1 protein expression level status was defined as“Neg” or “Pos” based on Western Blot results. p value <0.05 isconsidered as significant correlation.

7.1.3 Xenograft Models

Tumor samples from primary patient biopsies are propagated inimmunocompromised animals to create an animal model that may moreclosely resemble the human disease (e.g. John et al, Clin. Cancer Res.17(1):134-141 (2011); de Plater et al, Br. J. Cancer 103(8): 1192-1200(2010)). Tumors from lung cancer patient biopsies propagated in vivo arecharacterized for the mutational status of LKB1 by gene sequencingtechniques. In addition, the expression of the protein in these samplesis analyzed by Western blot techniques, IHC, or IF. Four of these canceranimal models are chosen, two that express wild type LKB1 and two thatexpress mutant LKB1, to confirm that the LKB1 mutant tumor models aremore sensitive to TORK inhibition compared to the wild type. A compoundas described herein (e.g. Compound 1) is tested in these xenograftmodels derived from primary human cancer biopsies, for example lungcancer biopsies. Compounds provided herein show or are expected to showincreased activity in xenograft models that express mutant LKB1.

The embodiments disclosed herein are not to be limited in scope by thespecific embodiments disclosed in the examples which are intended asillustrations of a few aspects of the disclosed embodiments and anyembodiments that are functionally equivalent are encompassed by thepresent disclosure. Indeed, various modifications of the embodimentsdisclosed herein are in addition to those shown and described hereinwill become apparent to those skilled in the art and are intended tofall within the scope of the appended claims.

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

What is claimed is:
 1. A method for treating non-small cell lungcarcinoma, comprising administering an effective amount of a TOR kinaseinhibitor to a patient having non-small cell lung carcinomacharacterized by a LKB1 gene loss, LKB1 protein loss, LKB1 genemutation, or LKB1 protein mutation, relative to wild type, wherein theTOR kinase inhibitor is a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more alkoxy orhydroxyalkyl groups.
 2. A method for treating non-small cell lungcarcinoma, comprising screening a patient's carcinoma for the presenceof a LKB1 gene loss, LKB1 protein loss, LKB1 gene mutation, or LKB1protein mutation, relative to wild type, and administering an effectiveamount of a TOR kinase inhibitor to the patient having non-small celllung carcinoma characterized by a LKB1 gene loss, LKB1 protein loss,LKB1 gene mutation, or LKB1 protein mutation, wherein the TOR kinaseinhibitor is a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more alkoxy orhydroxyalkyl groups.
 3. A method for treating non-small cell lungcarcinoma, comprising administering an effective amount of a TOR kinaseinhibitor and an effective amount of one or more agents that modulateAMP levels, glucose uptake, metabolism or a stress response to a patienthaving non-small cell lung carcinoma, wherein the TOR kinase inhibitoris a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more alkoxy orhydroxyalkyl groups.
 4. A method for treating non-small cell lungcarcinoma, comprising administering an effective amount of a TOR kinaseinhibitor to a patient having non-small cell lung carcinomacharacterized by an AMPK gene loss, AMPK protein loss, AMPK genemutation, or AMPK protein mutation, relative to wild type, wherein theTOR kinase inhibitor is a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more alkoxy orhydroxyalkyl groups.
 5. A method for treating non-small cell lungcarcinoma, comprising screening a patient's carcinoma for the presenceof an AMPK gene loss, AMPK protein loss, AMPK gene mutation, or AMPKprotein mutation, relative to wild type, and administering an effectiveamount of a TOR kinase inhibitor to the patient having non-small celllung carcinoma characterized by an AMPK gene loss, AMPK protein loss,AMPK gene mutation, or AMPK protein mutation, wherein the TOR kinaseinhibitor is a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more or hydroxyalkylgroups.
 6. A method for treating non-small cell lung carcinoma,comprising administering an effective amount of a TOR kinase inhibitorto a patient having non-small cell lung carcinoma characterized by areduced level of pAMPK protein, AMPK activity, or both, relative to wildtype, wherein the TOR kinase inhibitor is a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more or hydroxyalkylgroups.
 7. A method for treating non-small cell lung carcinoma,comprising screening a patient's carcinoma for the presence of a reducedlevel of pAMPK protein, AMPK activity, or both, relative to wild type,and administering an effective amount of a TOR kinase inhibitor to thepatient having non-small cell lung carcinoma characterized by a reducedlevel of pAMPK protein, AMPK activity, or both, wherein the TOR kinaseinhibitor is a compound of Formula (Ie):

or a pharmaceutically acceptable salt, stereoisomer, or tautomer,thereof, wherein: L is a direct bond; R¹ is substituted or unsubstitutedpyridine; and R² is substituted or unsubstituted cyclohexyl, whereinsubstituted groups can be substituted with one or more alkoxy orhydroxyalkyl groups.
 8. The method of claim 1, wherein R¹ is substitutedpyridine.
 9. The method of claim 2, wherein R¹ is substituted pyridine.10. The method of claim 3, wherein R¹ is substituted pyridine.
 11. Themethod of claim 4, wherein R¹ is substituted pyridine.
 12. The method ofclaim 5, wherein R¹ is substituted pyridine.
 13. The method of claim 6,wherein R¹ is substituted pyridine.
 14. The method of claim 7, whereinR¹ is substituted pyridine.